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Anti-HIV Agents: Current Status and Recent Trends

  • Athina Geronikaki
  • Phaedra Eleftheriou
  • Vladimir Poroikov
Chapter
Part of the Topics in Medicinal Chemistry book series (TMC, volume 29)

Abstract

Human immunodeficiency virus is responsible for acquired immunodeficiency syndrome (AIDS), an infectious disease that consists a serious concern worldwide for more than three decades. By the end of 2013 UNAIDS estimated that there were 35 million (range 33.2–37.2 million) adults and children living with HIV/AIDS worldwide. Despite the introduction of highly active antiretroviral therapy (HAART), the need for new anti-HIV agents is extremely high because the existing medicines do not provide the complete curation and exhibit serious side effects, and their application leads to the appearance of resistant strains. This chapter explores the medicinal chemistry efforts that gave rise to currently launched drugs as well as investigational anti-HIV agents. Currently used and studied molecular targets of antiretrovirals and the main classes of HIV-1 inhibitors are presented. Among the future prospects, we discuss the efforts directed to overcome the latent HIV infection, utilization of natural products as potential anti-HIV agents, recent trends on development of biologics as potential anti-HIV medicines, and application of computer-aided methods in the discovery of new anti-HIV drugs.

Keywords

Anti-HIV medicines Computer-aided drug design and discovery HAART HIV/AIDS Natural products New antiretroviral agents Pharmacological targets TAR Tat-binding drugs 

1 Introduction

Human immunodeficiency virus (HIV) is the cause of acquired immunodeficiency syndrome (AIDS), an infectious disease that consists a serious concern worldwide for more than three decades. Although the first recognized cases of AIDS were referred in the USA in 1981, it is now believed that the first incident occurred much earlier, in 1959 or even 1930, as it was proved by the detection of HIV virus in blood and tissue samples of humans who had died in that period [1, 2, 3]. According to the origin of most of these samples, the place of first known infections is Central or West Africa. So, although AIDS now concerns all countries of the world, it originally occurred in tropical areas.

HIV is a lentivirus of the larger group of retroviruses and has significant similarity with the simian immunodeficiency virus (SIV) that affects monkeys [4]. Because of the great resemblance between certain strains of SIV virus and the HIV-1 or HIV-2 types, it is now considered that HIV is a descendant of SIV [4, 5, 6, 7].

Precaution measures reduced the number of new infections referred each year, worldwide, from about 3.4 million in 2001 to about 2.4 million in 2012 [8]. By the end of 2013 UNAIDS estimated that there were 35 million (range 33.2–37.2 million) adults and children living with HIV/AIDS worldwide. Despite the introduction of highly active antiretroviral therapy (HAART), the number of people living with AIDS remains high, with a slight, constant increase leading to about 32 million patients in 2012 from about 29 million patients in 2001 [8]. This increase may reflect the higher survival of infected people as more potent therapeutic approaches are developed. Unfortunately, existing therapeutic agents can only diminish the viral load but fail to eliminate the virus completely. The need for long-time treatment of infected patients facilitates the development of resistant strains of the virus while also underlines the requirement of low side effect therapies. Consequently, although many anti-HIV drugs are already in the market [9, 10, 11, 12], research for the development of novel effective drugs with better efficacy, less side effects, and effective against the resistant strains continues [13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23].

2 The Biology of HIV

2.1 Structure and Organization

HIV belongs to the family of Retroviridae, subfamily of Lentivirinae [24, 25, 26]. It is a virus with a long incubation period, capable of infecting nondividing cells.

Following the typical pattern of retroviruses, the HIV genome consists of two copies of a single-stranded, positive-sense ribonucleic acid (RNA) of about 9.7 kilobases (Fig. 1). Each RNA molecule contains nine genes that code for the fourteen proteins of the virus (Fig. 2). The RNA is protected in a bullet-shaped capsid formed by about 2,000 molecules of the viral protein p24. The viral capsid is surrounded by molecules of the matrix protein p17, also known as membrane-associated (MA) viral protein. The outer layer of the virus consists of a lipid bilayer, which has been extracted by the host cell during budding of the newly formed virus. This membrane constitutes the viral envelope. The viral envelope carries a number of proteins with both virus and host-cell origin. The host-cell major histocompatibility complex (MHC) proteins and actin remain embedded within the viral envelope. The envelope consists of the viral transmembrane protein gp41 which forms non-covalent complex with the viral outer membrane glycoprotein gp120. Protein gp120 may separate from the envelope and can be detected in the serum or within the lymphatic tissue of HIV-infected patients. The envelope protein is the most variable component of HIV. It is structurally divided into highly variable (V) and more constant (C) regions. The variability of V regions seems to be related with envelope functionality and may affect co-receptor use. Three reading frames coexist, permitting existence and expression of overlapping gene-coding regions (Fig. 2).
Fig. 1

The structure of HIV virus

Fig. 2

Structure of HIV genome, transcription, translation and proteolysis products

2.2 HIV Life Cycle

HIV cannot replicate outside human cells. The HIV replication cycle can be summarized in six steps: (1) binding and entry, (2) uncoating, (3) synthesis of viral DNA, (4) integration of viral DNA in host DNA, (5) virus protein synthesis and assembly, and (6) budding (Fig. 3).
Fig. 3

HIV life cycle. The main drug targets are indicated in yellow

The proteins essential for virus recognition and entry into target cells are the heterodimer proteins gp120 and gp41, present on the viral envelope. The gp41 subunit contains a hydrophobic moiety at its amino terminus, which has an important role in fusion of the viral and cellular membranes [27]. HIV gp120 binds to CD4a, a glycoprotein present on the cell surface of about 60 % of the circulating T lymphocytes, on the T-cell precursors within the bone marrow and thymus and on monocytes/macrophages, eosinophils, dendritic cells, and microglial cells of the central nervous system. During T-cell recognition of a foreign antigen, the CD4 molecule functions as a co-receptor of the major histocompatibility complex class II [28]. A second co-receptor is also required for viral entry. Such co-receptors may be the CC chemokine receptor 5 (CCR5), the CXC chemokine receptor 4 (CXCR4), and other proteins of the class of seven-transmembrane region receptors [29, 30, 31, 32, 33, 34]. After binding of the viral gp120 protein to the CD4 receptor and to the co-receptor, a conformational change in the gp41 protein leads to the insertion of the N-terminal hydrophobic part of the protein into the host-cell membrane [35]. This insertion results in the fusion of the viral and host-cell membranes and to the subsequent entry of the viral contents into the host-cell cytoplasm.

Following membrane fusion, the virus loses the capsid, liberating the viral RNA (uncoating). At the next stage, the viral RNA is used as a template for the synthesis of the proviral DNA by the action of reverse transcriptase (RT) which contains three active sites: a reverse transcriptase, an RNase H, and a DNA polymerase active site. As a first step, RT begins the reverse transcription of viral RNA, through its RNA-dependent DNA polymerase (reverse transcriptase) activity. This leads to the production of a RNA/DNA hybrid double helix. At a second step, RT hydrolyzes the RNA strand of the hybrid, via the RNase activity of the enzyme. At a third step, the DNA-dependent DNA polymerase active site of the enzyme synthesizes the complementary DNA strand to form a double helix DNA molecule. The dsDNA molecule is then integrated within the genome of the host cell by the integrase. This enzyme cleaves nucleotides of each 3′ ends of each strand of the double helix DNA producing two sticky ends and catalyzes its integration into the host genome. Since the expression of viral proteins require the activation of target cells, monocytes/macrophages, microglial cells, and infected quiescent CD4+ T cells contain integrated provirus genome and represent long-living cellular reservoirs of HIV [36].

Upon cell activation, transcription of the integrated proviral DNA occurs. The three reading frames enable the expression of the 14 viral proteins, although the genetic information for their synthesis is overlapping each other. The first proteins synthesized are the regulatory HIV-1 proteins Tat and Rev. Tat binds to the transactivation response (TAR site) element at the beginning of the HIV-1 RNA and stimulates the transcription and the formation of longer RNA transcripts. On the other hand, Rev induces the transcription of longer RNA transcripts and the expression of structural and enzyme genes and inhibits the production of regulatory proteins. The viral mRNA migrates into the cytoplasm where proteins are synthesized. During the translation process, large precursor protein molecules are produced which are then cleaved by the HIV-1 protease to produce the functional viral proteins. So, the precursor gp160 protein, derived from the env gene, is hydrolyzed into the gp120 and gp41 envelope proteins. The Gag and Pol proteins are also derived from large precursor molecules, from which the HIV protease cleaves the p24, p17, p9, and p7 gag final products and the viral protease, reverse transcriptase, and integrase, which are the Pol final products, respectively.

The formation of the new viral particles is a stepwise process: two viral RNA strands associate together with viral enzymes, and core proteins assemble over them forming the virus capsid. The capsid then migrates toward the cell surface. During the budding process, the viral envelope lipid membrane is formed by extracting phospholipids and cholesterol from the host cell.

2.3 HIV Types

Based on genome sequence, two types of HIV virus are distinguished: HIV-1 and HIV-2. Both types can cause AIDS, although they have differences in pathogenesis. HIV-2 is less virulent than HIV-1, and HIV infection takes longer to progress to AIDS. However, HIV-2 more frequently attacks the central nervous system [37].

3 The Main Classes of Anti-HIV Drugs

The efforts for the development of effective anti-HIV drugs have been focused on several target molecules of viral or host-cell origin. The launched anti-HIV agents belong to two main categories: viral enzyme inhibitors and fusion/entry inhibitors.

3.1 Viral Enzyme Inhibitors

The HIV enzymes were among the first drug targets. The first drug belonged to the family of nucleoside analogs of reverse transcriptase (RT) inhibitors (NRTIs). Zidovudine (Retrovir) was approved in 1987. Drugs of this class are mimicking the dNTPs, the natural substrates of the enzyme, thus inhibiting reverse transcription or viral RNA to DNA. The first molecule of a second family of RT inhibitors is the non-nucleoside reverse transcriptase inhibitors (NNRTIs). The first drug of this class nevirapine (Viramune) was approved in 1996. This kind of inhibitors acts by binding to allosteric site of the enzyme. The first HIV-1 protease-inhibitor saquinavir mesylate (Invirase) was approved in 1995, while the first inhibitor of HIV-1 integrase raltegravir was approved only in 2007 (Table 1).
Table 1

Categories of anti-HIV drugs

Drug target

Antiretroviral drug class

Approved and experimental drugs

First approved

Mechanism of action

Nature

Name

Viral enzymes

Viral reverse transcriptase (HIV-1 RT)

Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs, nucleoside analogs, nukes)

Small organic molecule

Abacavir, emtricitabine, tenofovir, zidovudine, lamivudine, stavudine

1987

NRTIS mimic natural dNTPs and inhibit reverse transcription of viral RNA to DNA

Non-nucleoside reverse transcriptase inhibitors (NNRTIs, non-nucleosides, non-nukes)

Small organic molecule

Efavirenz, etravirine, nevirapine

1996

NNRTIs inhibit viral reverse transcriptase protein by binding to an allosteric center of the enzyme

Nucleotide-competing RT inhibitors (NcRTIs)

Small organic molecule

INDOPY-1, DAVPs

Non-nucleotide RT inhibitors (NNRTIs) which exhibit competitive mode of inhibitory action against dNTPs

Viral protease

Protease inhibitors (PIs)

Small organic molecule

Ritonavir, nelfinavir, amprenavir, lopinavir, atazanavir, tipranavir, darunavir

1995

PIs inhibit viral protease, involved in maturation of viral enzymes

Viral integrase

Integrase inhibitors

Small organic molecule

Raltegravir, elvitegravir, dolutegravir

2007

Integrase inhibitors interfere with the integrase enzyme, which HIV needs to insert its material into human cells

Viral transmembrane envelop protein pg41

Fusion inhibitors

Oligopeptide

Enfuvirtide

2003

Fusion or entry inhibitors prevent HIV from binding to or entering human immune cells

Host-cell secondary co-receptor CC chemokine receptor 5 (CCR5)

Entry inhibitors

Small organic molecule

Maraviroc

2007

Host-cell CD4

Entry inhibitors

Humanized antibody

Ibalizumab

2014

3.2 Fusion or Entry Inhibitors

Drugs that prevent entering of the virus to the host cells are known as fusion or entry inhibitors. This kind of inhibitors may interact either with the viral transmembrane envelope protein gp120 or gp41, which has an essential role in viral entrance into the host cell, or bind to certain molecules of the host-cell surface that act as co-receptors (Fig. 4, Table 1).
Fig. 4

HIV virus binding to the host cell

4 Current State of Anti-HIV Therapy and Recent Studies

4.1 HIV-1 Reverse Transcriptase (RT) Inhibitors

HIV-1 reverse transcriptase inhibitors inhibit the viral enzyme, which catalyze the reverse transcription of viral RNA to DNA.

The active form of the enzyme is a heterodimer composed of two subunits, p66 and p51. The p51 subunit has identical sequence with part of the p66 subunit but a different 3D structure. So, while p51 has a structural function, the p66 subunit contains the catalytic sites of the enzyme, a polymerase active site, and an RNase H active site [38]. Three distinct enzymatic activities were found in RT: (a) an RNA-dependent DNA polymerase activity where the synthesis of the negative strand of the proviral DNA takes place, (b) an RNase H activity which is responsible for the degradation of the RNA portion of the RNA/DNA hybrid, and (c) a DNA-dependent DNA polymerase activity that catalyzes the synthesis of the positive DNA strand. The RNase H activity is also involved in the removal of the tRNA primer that is used to initiate synthesis of the first strand [39, 40]. After synthesis of the first DNA strand, the genomic retroviral RNA template is cleaved into multiple fragments, one of which, a 19-base RNA primer with a purine-rich sequence, is used by the reverse transcriptase as a primer [41].

The structure of HIV-1 RT is shown in Fig. 5 [42, 43]. The N-terminal portion of the p66 subunit attains a structure that resembles an open right hand containing three domains, known as: fingers, palm, and thumb [44, 45]. Polymerase active site is placed in this domain, while RNase H active site is located in the C-terminal part of RT.
Fig. 5

HIV-1 reverse transcriptase structure from (PDB ID: 3KLF) [44, 45]

The approved RT inhibitors belong to two families: the nucleoside/nucleotide RT inhibitors (NRTIs) and the non-nucleoside RT inhibitors (NNRTIs). A novel group of inhibitors characterized as nucleotide-competitive RT inhibitors (NcRTIs) also exist.

4.1.1 Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

The nucleoside reverse transcriptase inhibitors (NRTIs) were among the first medicines approved for anti-HIV treatment. Abacavir (Ziagen), emtricitabine (Emtriva), tenofovir (Viread), zidovudine (Retrovir), lamivudine (Epivir), and stavudine (Zerit) belong in this category.

The NRTIs are prodrugs that are structurally similar to the endogenous deoxynucleosides, with structural substitutions of the 3′ OH group of deoxyribose. After insertion into host target cells, NRTIs are phosphorylated by kinases of the host cell to form their active triphosphate derivatives (ddNTPs). Since NRTIs lack a 3′ hydroxyl group on their ribose or ribose mimic moiety, the synthesis of the DNA strand is terminated after incorporation of nucleotide mimic-drug derivative in the newly synthesized DNA strand. In practice, the drugs’ triphosphates inhibit HIV RNA reverse transcription through two mechanisms [46, 47, 48, 49]. Firstly, their phosphorylated and non-phosphorylated forms act as competitive inhibitors of the enzyme against dNTPs, while at a second phase they stop DNA elongation after incorporation.

Representative structures of NRTIs are shown in Fig. 6.
Fig. 6

FDA-approved NRTIs. AZT zidovudine, ddI didanosine, ddC zalcitabine, D4T stavudine, 3TC lamivudine, FTC emtricitabine, ABC abacavir sulfate, PMPA tenofovir disoproxil fumarate

This kind of medicines is not associated with the high rate of resistance development. However, a few strains resistant to NRTIs have been developed. The active site of reverse transcriptase is shown in Fig. 7a. The amino acid residues surrounding the active center, which are mutated in resistant strains, are presented in the picture. Amino acid residues located in the same position of resistant strains are shown in brackets.
Fig. 7

(a) Active and (b) allosteric site of HIV-1 RT. Amino acid residues involved in interaction with the inhibitors and subject to mutations are indicated with yellow color on HIV-1 reverse transcriptase complex with the NNRTI, nevirapine (PDB ID: 3V81). Amino acid residues present at the same position in resistant strains are shown in brackets [44, 45]

Undesired Side Effects of NRTIs

NRTIs are often related with undesired side effects, mainly derived from the NRTI-induced inhibition of the mitochondrial DNA polymerase gamma [50]. Among the disorders associated with long-term use of NRTIs are hematologic disorders, peripheral neuropathies, myopathy, and cardiotoxic and hepatotoxic effects [51]. Increased levels of lactate in blood and lactic acidosis are observed because of the toxic effect [52, 53]. NRTIs have also been associated with peripheral lipodystrophy [54, 55, 56].

4.1.2 Non-nucleoside RT Inhibitors (NNRTIs)

As crystallographic studies have revealed, NNRTIs bind to an allosteric center that is located near the RNA-dependent polymerase active site of the enzyme on subunit p66 (Fig. 7b) [57, 58, 59, 60, 61]. The allosteric center of the enzyme is formed by a hydrophobic cleft surrounded by the aromatic amino acid residues Tyr181, Tyr188, Phe227, Trp229, and Tyr318 and the hydrophobic amino acid residues Pro95, Leu100, Val106, Val108, Val179, Leu234, and Pro236 [62]. Apart from hydrophobic and aromatic π–π interactions, which are essential for RT-inhibitor complex stabilization, hydrogen bonds with Lys101 or Lys103 are formed in many cases. This may be the reason for the >50 % of mutations of Lys103 in resistant strains. Crystallographic studies of the first-generation NNRTIs indicated that a butterfly conformation (Fig. 8) of the molecules favored binding. The ability to adapt this conformation was considered as mandatory for effective compounds [62, 65]. However, inhibitors with different conformations, such as the 4-dihydroquinoxalin-2(1H)-thione derivative, HBY097, were also found to interact with the active site [66]. Moreover, flexible molecules, capable of acquiring multiple conformations, like etravirine, were found to present inhibition activity against more mutated strains [67]. The allosteric center is practically absent in RT enzyme and is created after interaction with the inhibitor [68].
Fig. 8

3D structure of (a) nevirapine (PDB ID: 1S1X) and (b) efavirenz (PDB ID: 1FK9) in complex with RT [45, 63, 64]

All approved and most of the investigated NNRTIs exhibit a noncompetitive mode of action. However, for a few NNRTIs different modes of actions have been described. The bis(heteroaryl)piperazine inhibitor (BHAP), U-90152E, acts as a mixed inhibitor with respect to the template: primer and dNTP and for both the RNA- and DNA-directed DNA polymerase activities of the enzyme [69] while chloroxoquinolinic ribonucleoside, 6-chloro-1,4-dihydro-4-oxo-1-(beta-d-ribofuranosyl) quinoline-3-carboxylic acid, was found to inhibit RT with an uncompetitive mode of action with respect to dTTP and a noncompetitive mode of action with respect to RNA: primer template [70]. (4/6-Halogen/MeO/EtO-substituted benzo[d]thiazol-2-yl) thiazolidin-4-one derivatives were found to act as uncompetitive inhibitors or competitive inhibitors against dNTPs depending on the substitution [71].

Commercially available NNRTIs are compounds bearing a variety of heterocyclic rings such as benzoxazin-2-one (efavirenz), dipyrido[1,4]diazepine-6-one (nevirapine), pyrimidine (etravirine) [72], piperazine, and indolyl (delavirdine) moieties [73, 74]. Reverse transcriptase inhibition potency differs among the inhibitors. Apart from molecules having received FDA acceptance (Fig. 9), many compounds have been found to exhibit RT inhibitory action [66, 68, 75, 76, 77, 78, 79] such as benzothiazine dioxides [80], N1,N3-disubstituted uracils [81], 6-arylmethyl-substituted S-DABOs [82], indolyl aryl sulfones [83], 2-adamantyl-substituted thiazolidin-4-ones [84], lectins [85], and many others [10, 86, 87, 88, 89, 90, 91, 92, 93]. Representative structures of these inhibitors are shown in Fig. 10.
Fig. 9

FDA-approved NNRTIs

Fig. 10

Structure of compounds with the RT inhibitory activity

Though all approved NNRTI have different chemical structures, all of them contact the same site in the RT structure. Therefore, a mutation providing resistance to one NNRTI also provides resistance to all other NNRTIs (“cross resistance”) [94, 95, 96]. Amino acid residues of the allosteric site, which are subject to mutations, are indicated in Fig. 7b. Amino acid residues located in the same position of resistant strains are shown in brackets.

Undesired Side Effects of NNRTIs

Non-nucleoside RT inhibitors do not present the same side effects as NRTIs but are related with high frequencies of resistance development. Undesired side effects are also associated with the use of NNRTIs, adding the goal of finding lower toxicity agents among the research targets [97, 98]. NNRTIs may also cause rash, Stevens–Johnson syndrome and toxic epidermal necrolysis. More specifically, efavirenz is associated with symptoms of the central nervous system disorders and fatigue and may also affect liver function and induce hyperlipidemia. Etravirine and nevirapine have been also related to liver disorders.

4.1.3 Nucleotide-Competing RT Inhibitors (NcRTIs)

Νon-nucleotide/non-nucleoside RT inhibitors (NNRTIs) which do not incorporate into the newly synthesized DNA strand but exhibit competitive mode of inhibitory action against dNTPs belong to a different category and have been proposed to be called as nucleotide-competing RT inhibitors (NcRTIs) [99]. Among these inhibitors, 5-methyl-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H pyrido[3,2-b]indole-3-carbonitrile (INDOPY-1) (Fig. 11) inhibits RT with a competitive [100] or mixed-type [101] mode with respect to dNTPs and seems to interact with the amino acid residues involved in dNTPs associations such as Met184 and Tyr115. 4-Dimethylamino-6-vinylpyrimidines (DAVPs) also compete with the incoming dNTP [102, 103]. They bind to an RT site distinct from the NNRTI-binding pocket and close to the RT polymerase catalytic site [104]. This site comprises from the amino acid residues Met230, Gly231, Gly262, Lys263, Trp266, Met184, and Asp186 (Fig. 12).
Fig. 11

Representative structures of NcRTIs: 5-methyl-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile (INDOPY-1 left) and 6-ethenyl-N,N-dimethyl-N,N-dimethyl-2-(methylsulfonyl)-4-pyrimidamine (DAVP right)

Fig. 12

HIV-1 reverse transcriptase complex with the NcRTI, 4-dimethylamino-6-vinylpyrimidine (PDB ID: 3ISN) [104]

4.2 HIV-1 Integrase Inhibitors

HIV integrase is a promising drug target for HIV treatment because of its central role in the HIV life cycle and the absence of analog enzymes in human organism. Integrase is a 32 kDa protein that acts as a tetramer (Fig. 13) [105].
Fig. 13

3D structure model of HIV-1 integrase (PDB ID: 1K6Y) [105]

Like all retroviral integrases, the HIV integrase contains three domains: an N-terminal – Zinc-binding domain, consisted by three helices – a catalytic domain, and a C-terminal DNA-binding domain surrounded by the amino acid residues Thr66 and Glu92 [106]. Retroviral IN catalyzes: (a) a process called 3′-end processing, in which two or three nucleotides are removed from one or both 3′ ends of the viral DNA to expose the invariant CA dinucleotides at both 3′-ends of the viral DNA, and (b) the strand-transfer reaction, in which the 3′ ends of the viral DNA are covalently ligated to the host chromosomal DNA. Both reactions are catalyzed by the same active site. Several host-cell proteins bind to HIV integrase, facilitating its action. Human chromatin-associated protein LEDGE is one of them. LEDGE interacts with HIV integrase at the area of amino acid residues Thr124 and Glu170 (Fig. 14) [107].
Fig. 14

HIV-1 integrase complex with the peptide LEDGE (brown and green chains). PDB ID: 3AVA [107]

Investigation for the finding of integrase inhibitors led to the development of inhibitors [108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130] that bind to either the catalytic site [109] or an allosteric site (Fig. 15) [110]. Allosteric inhibitors, such as the (2S)-2-tert-butoxy-2-[4-(4-chlorophenyl)-6-(3,4-dimethylphenyl)-2,5-dimethyl-3-pyridyl]acetic acid, LF8, are found to occupy the LEDGE interaction site (Fig. 15b). However, most of the inhibitors found and the FDA-approved integrase inhibitors are molecules that bind to the active site of the enzyme.
Fig. 15

(a) HIV-1 integrase catalytic core complex with 2-amino-6-fluorobenzothiazole (PDB ID: 3VQ9). Amino acid residues at the same position of the resistant strains are shown in brackets [82]. (b) HIV-1 complex with the allosteric inhibitor (2S)-2-tert-butoxy-2-[4-(4-chlorophenyl)-6-(3,4-dimethylphenyl)-2,5-dimethyl-3-pyridyl]acetic acid (PDB ID: 4O0J) [110]

The first integrase inhibitor received FDA approval in October 2007 for the treatment of HIV-1 as part of combination antiretroviral therapy. This first approved drug of this category was raltegravir (RAL) (Fig. 16). Two other integrase inhibitors have been approved for the treatment of HIV till now: elvitegravir (ELV) and dolutegravir (DTG).
Fig. 16

Integrase inhibitors (INIs)

Raltegravir is a 1-N-alkyl-5-hydroxypyrimidinone [127]. It is a structural analogue of the diketo acid class of inhibitors [114, 127]. It possesses metal-chelating functions and can interact with the divalent metals Mg2+ or Mn2+ within the active site of HIV-1 integrase (Fig. 17) [128].
Fig. 17

Probable mechanism of action of integrase inhibitors bound to the active site of the enzyme [105]

Raltegravir has an IC50 value of approximately 10 nM and is active on many different HIV-1 and HIV-2 virus strains.

Elvitegravir is a dihydroquinoline carboxylic acid compound that also posses the β-hydroxyketone structural motif [129]. This drug is active against HIV-1 and HIV-2, with an IC90 of 1.2 nM in peripheral blood mononuclear cells (PBMCs), and an IC50 of 0.2 nM. Elvitegravir was licensed by Tokyo Tobacco in 2008 and was approved by FDA in the USA in 2012.

Dolutegravir [130] was approved for the treatment of HIV in 2013 in the USA and Canada and in 2014 in Europe.

MK-2048 [126] belongs to the second generation of integrase inhibitors that are currently under development. MK-2048 is more potent than raltegravir, and it is being investigated for use as part of preexposure prophylaxis (PrEP).

Despite the achievements in the design of effective integrase inhibitors, the development of resistant strains is still an essential limitation to use these drugs for antiretroviral therapy. Resistance to both raltegravir and elvitegravir as well as to dolutegravir has been observed [112, 121, 126, 127, 128]. Since all approved INIs practically have the same mode of action, through binding at the catalytic site of the enzyme of INSTIs, a number of virus strains appeared with mutations that enable resistance to two or three approved integrase inhibitors. Therefore, the design and discovery of other classes of integrase inhibitors with a mechanism of action distinct from that of INSTIs still represents a highly attractive antiretroviral strategy.

There are many reports in the literature regarding HIV-1 IN inhibitors tested in vitro [129, 130, 131], but most of them did not exhibit antiviral activity in cell culture or have not appropriate selectivity indices. Furthermore, even if most of them show antiviral effect, it is not clear if the integration step is really targeted.

Pannecouque et al. [132] studied 5-(4-substituted-phenyl)-5-H-pyrano[2,3-d:-6,5-d]dipyrimidines (PDPs) as inhibitors of viral integration in cell culture. They found that compound V-165 or 5-(4-nitrophenyl)-2,8-dithiol-4,6-dihydroxy-5H-pyrano[2, 3-d:-6,5-d′]dipyrimidine was not only exhibiting an EC50 of 8.9 μM but was also active against HIV-1 (NL4.3 and L1), HIV-1 (NDK, NL4.3, and L1) strains, HIV-2 (ROD and EHO), and SIV (MAC251), at EC50 values in range 3.7–30 μΜ. Based on the obtained results, the authors concluded that V-165 could be a lead compound for further synthesis and development of novel HIV drugs for combination therapy.
The search for new integrase inhibitors is continued. In 2009 Brzozowski et al. [133] reported the synthesis and biological evaluation of a series of novel 3-aroyl-2,3-dihydro-1,1-dioxo-1,4,2-benzodithiazines (Fig. 18). All the compounds 13 inhibited IN-mediated strand-transfer reaction with IC50 values ranging from 3 to 30 μM. The studies on mutants revealed that the Y99S mutant in general was about fivefold more resistant than the H114A. This implies that the tested compounds most likely bind to these novel sites.
Fig. 18

Structures of 3-aroyl-2,3-dihydro-1,1-dioxo-1,4,2-benzodithiazines (1), tricyclic N-hydroxy-dihydronaphthyridinones (2), and carbamoyl pyridines (3)

Johnson et al. [134] reported the synthesis of novel tricyclic N-hydroxy-dihydronaphthyridinones (2) as potent, orally bioavailable HIV-1 integrase inhibitors. The evaluation of integrase inhibitory activity showed that IC50 of N-hydroxy-dihydronaphthyridinones is in range between 2.9 and 250 nM. It was found that antiviral activity in cell assays is comparable to the currently marketed HIV-1 integrase inhibitor raltegravir (EC50 10 nM).

Kawasuji et al. [135] reported their studies on new carbamoyl pyridines (3) for their chelating properties in order to design new compounds with improved pharmacokinetic (PK) and resistance profile. Thus, the designed compounds with carbamoyl pyridone nucleus appeared to be good inhibitors in enzymatic as well as in antiviral assays with IC50 values in nanomolar range. Furthermore, these compounds being administered to rats, dogs, and monkeys exhibited good PK profile.

Tsiang et al. [136] aimed to test tert-butoxy-(4-phenyl-quinolin-3-yl)-acetic acids (Fig. 19), which were shown to be analogues to LEDGINs in order to explicate their mechanism of action. This study revealed that tBPQAs appear to be potent inhibitors of HIV-1 replication with EC50 values of 10–20 nM. For this study a variety of infected cells including primary PBMC were used. Regarding mechanism of tBPQAs’ action, authors showed that these compounds could be inhibitors of HIV-1 integration through binding to the IN dimer interface. It was also shown that they could be dual inhibitors, since they are responsible for loss of flexibility of IN dimer, which did not allow correct assembly of viral DNA-IN complex. On the other hand, it inhibits the interaction of IN with LEDGF.
Fig. 19

Structure of tert-butoxy-(4-phenyl-quinolin-3-yl)-acetic acids

4.2.1 Side Effects of Integrase Inhibitors

There are some common side effects reported in the literature such us creatinine kinase elevations, myopathy, and some others [120, 121]. Thus, common side effects of elvitegravir include diarrhea, while common side effects of dolutegravir include insomnia and headache. Serious side effects also include allergic reactions and abnormal liver function in patients who were simultaneously infected with hepatitis B or C.

4.3 HIV-1 Protease Inhibitors

HIV protease is an aspartate protease. Although similar to other aspartate proteases of human organism, its action in HIV replication is essential and cannot be replaced by proteases of the host cell [114, 115, 137, 138]. HIV protease consists of two identical protein subunits. The active site of the enzyme is placed between the two subunits at the area of amino acid residues Asp25, Thr26, and Gly27 of the first and Asp25′, Thr26′, and Gly27′ of the second subunit (Fig. 20). Peptide-like compounds have been used since the 1990s as HIV protease inhibitors, exhibiting competitive inhibition activity. These drugs inhibit proteolytic cleavage of HIV Gag, Pol, and Env polyproteins to the active proteins of the virus [140, 141].
Fig. 20

3D structure of HIV-1 protease complex with fosamprenavir (PDB ID:3S85) Yellow lines represent amino acid residues involved in interactions with inhibitors or amino acid residues which are mutated at resistant strains of the virus. The amino acid residues present at the same position of mutated strains are shown in brackets [139]

All the commercial HIV protease inhibitors (Table 2) consist of a central core of hydroxyethylene scaffold with the exception of tipranavir, whose central core is a coumarin [142, 143, 144, 145] (Fig. 21).
Table 2

HIV-1 protease inhibitors approved by FDA

Drug

Nature

Date approved by FDA

Saquinavir

Peptidomimetic

1995

Ritonavir

Peptidomimetic

1996

Nelfinavir

Nonpeptidic

1997

Amprenavir

Nonpeptide

1999

Lopinavir

Peptidomimetic

2000

Fosamprenavir

Phosphoester prodrug

2003

Atazanavir

Azapeptide

2003

Tipranavir

Nonpeptide

2005

Darunavir

Nonpeptide

2006

Fig. 21

Structures of the approved HIV protease inhibitors

Hydrogen bonds between hydroxyl groups of the inhibitor and the carboxylic acids of Asp25 and Asp25′ of the enzyme are involved in complex stabilization. Hydrogen bonds are also formed between a water molecule, which is linked to Ile50 and Ile50′ and carbonyl groups of the peptidomimetic inhibitors. Interactions with Ile50 residues of the enzyme are present in case of the non-peptidyl inhibitors as well. In general, the ability to form hydrogen bonds is essential for complex stabilization. In enzyme interaction with its natural substrate, four hydrophobic amino acid residues of the substrate are placed in four hydrophobic pockets of the enzyme. The existence of hydrophobic moieties capable to interact with these pockets in the molecule of inhibitors increases the potency of the inhibitor (Fig. 20).

Even though ritonavir was developed as HIV protease inhibitor, it is mostly used as a booster of other protease inhibitors. More specifically, because of its structural similarity with the known CYP3A inhibitors (Fig. 22), ritonavir acts as an inhibitor of cytochrome P450 3A4 (CYP3A4) that normally metabolizes protease inhibitors in the liver. Low doses of ritonavir can be used to enhance the other protease inhibitors [146].
Fig. 22

Structure of CYP3A inhibitor

Unfortunately, ritonavir and other protease inhibitors are associated with several side effects as well as development of HIV-resistant strains. The changes in amino acid residues in resistant strains are shown in Fig. 20 in brackets. Moreover, strains resistant to one PI may show resistance to other protease inhibitors as well (cross resistance). Thus, the development of novel inhibitors, with less adverse effects and ability to act on resistant mutants, is of major interest, and various groups have reported on their progress in this area [147].

Sperka et al. [148] based on the previous publications [149, 150] reported the synthesis of β-lactam derivatives and their evaluation as uncompetitive PIs. Authors [148] used a colorimetric microtiter plate method [151] to screen a 126-member combinatorial monocyclic beta-lactam library [152] for inhibition of the enzyme. It was found that several of the compounds exhibited more than 60 % inhibition that was proved for some compounds by HPLC method under the same assay conditions. The Ki values for the compounds were determined by HPLC method [153].

It should be mentioned that the type of inhibition depends on the conditions in which assay was performed. Thus, under low ionic strength conditions, the type of inhibition appeared to be uncompetitive, while at high ionic strength which is optimal for HIV protease [154, 155], the type of inhibition was mixed.

Analyzing these results, the authors believed that the inhibitor might interact with the closed flap region of the enzyme–substrate complex [148]. On the other hand, change in the type of inhibition at higher ionic strength may be due to the more favorable binding of these compounds to the active site of the enzyme through hydrophobic contact with the appropriate side chains [148]. The same was observed for peptidomimetic inhibitors, which bind much more strongly toward the active site of the enzyme in high ionic strength [145].

Cigler et al. [156] reported the potent, specific, and selective inhibition of HIV PR by parental and substituted metallacarboranes, namely, cobalt bis(1,2-dicarbollides). They provided evidence for the mechanism of action of these compounds, showed their antiviral activity in tissue cultures, analyzed their binding toward the enzyme by X-ray crystallography, and showed the potential of this class of compounds to become a novel pharmacophore for enzyme inhibition. Authors identified 12-vertex metallacarborane clusters as suitable hydrophobic, stable, and nontoxic structural analogues of aromatic compounds. These compounds showed good antiviral activity with IC50 values ranged from 0.13 to 1.4 μM.

Ghosh and Anderson [157] in their review presented the design of novel HIV-1 protease inhibitors with heterocyclic core scaffolds that have been reported in the recent years (2005–2010). They pointed out on the role that heterocycles play as scaffold and bioisosteres in HIV protease-inhibitor drug development. Some of them are shown in Fig. 23.
Fig. 23

PIs with the heterocyclic scaffolds

Wang et al. [158] reported the evaluation of anti-HIV activity of mangiferin. According to the authors, mangiferin (Fig. 24) can inhibit HIV-1IIIB-induced syncytium formation at noncytotoxic concentrations, with a 50 % effective concentration (EC50) at 16.9 μM and a therapeutic index (TI) above 140. It should be mentioned that inhibitory activity of this compound was dose dependent. Furthermore, it showed activity against (NNRTIs) resistant strain HIV-1A17 with EC50 22.75 μM.
Fig. 24

Structure of mangiferin

Jonckers et al. [159] reported the discovery of a novel class of benzoxazole and benzothiazole amides that were designed to have no other primary activity than CYP3A4 inhibition together with an acceptable toxicity/side effect profile.

A diverse set of benzoxazole and benzothiazole amide derivatives was obtained using a convenient synthesis (Scheme 1) and evaluated for their anti-HIV activity against wild-type HIV-1 which was studied on acutely infected lymphoblastic cell line (MT4-LTR EGTP) using gene assay [160]. None of the compounds showed significant activity with EC50 > 10 μΜ in each case.
Scheme 1

Synthesis of benzoxazole and benzothiazole amide derivatives as potential anti-HIV agents

Compounds were also tested for the CYP3A4 inhibition in vitro using a human liver microsome (HLM)-based assay in which conversion of midazolam to 10-OH-midazolam was measured (by LC/MS) in the presence and absence of the inhibitor. Fortunately, all compounds exhibited very good inhibitory activity with IC50 values in range from 0.022 to 2.7 μΜ. Analysis of the results revealed some structure–activity relationships. Thus, it was observed that overall, having a 5-thiazolyl fragment (R1) present in the molecule resulted, in most cases, in potent CYP3A4 inhibition, with the 3-pyridyl and 5-benzo[1,3]dioxolyl fragment as good alternatives. On the contrary, the 4-pyridyl group is clearly unfavorable as a tenfold loss in inhibitory potency was observed. It could be mentioned that the authors identified a novel class of CYP3A4-inhibiting benzoxazole and benzothiazole amides that are devoid of HIV protease-inhibiting activity following a key “sulfonamide-to-amide” switch.

4.3.1 Side Effects of Protease Inhibitors

Even protease inhibitors play an important role in antiretroviral therapy and have dramatically improved the life expectancy of HIV-infected individuals; they are also associated with abnormalities in glucose/lipid metabolism and body fat distribution. There is no clear picture regarding the pathogenesis of protease-inhibitor-associated metabolic and body fat changes and their potential treatment; thus, further studies are required. Many protease inhibitors have been accused for gastrointestinal disorders, increasing of bleeding, insulin resistance, hyperglycemia, and hyperlipidemia and have also been associated with increased incidents of coronary artery disease and lipodystrophy [161, 162, 163, 164, 165].

Moreover, there is a link between HIV-PI usage and increased ROS production as shown in the literature established by human [166]-, animal [167, 168, 169, 170]-, and cell-based studies [171, 172, 173, 174, 175], which include numerous cell and tissues.

4.4 HIV Fusion Inhibitors

The drugs of this class are responsible for binding, fusion, and entry of HIV virions into a human cell. They attached themselves to proteins of the surface of HIV virion or to proteins of the surface of CD4 cells. The US Food and Drug Administration (FDA) approved only two entry inhibitors.

The first one is Fuzeon (enfuvirtide) (Fig. 25), which is an oligopeptide, approved in March 2003, that targets the gp41 protein on HIV’s surface [176, 177, 178]. Apart from enfuvirtide, several other oligopeptides have been found to exhibit inhibitory action targeting at the same viral protein (Fig. 26).
Fig. 25

FDA-approved HIV entry inhibitors

Fig. 26

HIV-1 envelop glycoprotein gp41 complex with the fusion oligopeptide inhibitor sifuvirtide (PDB ID: 3VIE) [186]. Amino acid residues mutated at strains resistant to enfuvirtide are shown with yellow lines at the right structure. The residues at the same position of resistant strains are shown in brackets

The second category of entry inhibitors includes maraviroc, which acts as a negative allosteric modulator of the CCR5 co-receptor (Fig. 27). This drug avoids the association of HIV protein gp120 to the CCR5, thus blocking the entry of the virus into the host cell. However, HIV can also use the other co-receptors such as the CXCR4.
Fig. 27

CCR5 co-receptor complex with maraviroc (PDB ID: 4MBS) [179]

In a way similar to other drugs targeting to viral proteins, strains resistant to enfuvirtide have also been developed. The most common mutations leading to resistance involve the amino acid residues 36–45 of gp41 such as Gly361→Asp, Ser, Val, or Glu; Val38→Ala, Glu, or Met; Gln40→His; Asn42→Thr; and Asn43→Asp [180, 181, 182, 183, 184, 185] (Fig. 26).

Experimental drugs include Schering-Plough’s CCR5-blocking entry inhibitor vicriviroc, Progenics’s CCR5-blocking monoclonal antibody PRO 140, and Tanox’s TNX-355, a drug that targets the CD4 protein on CD4 cells.

Since only two drugs were approved by FDA as fusion inhibitors and taking into account that this is an important target in the battle against HIV, scientific community continued the search for new potent fusion inhibitors. Jiang et al. [187] based on their previous works [188, 189] on the synthesis of N-(4-carboxy-3-hydroxy)phenyl-2,5-dimethylpyrrole (1) and N-(3-carboxy-4-chloro)phenylpyrrole (2) as well as series of 2-aryl-5-(4-oxo-3-phenethyl-2-thioxothiazolidinylidenemethyl)furans (3a-o) reported the synthesis of new 5-((arylfuran/1H-pyrrol-2-yl)methylene)-2-thioxo-3-(3-(trifluoromethyl) phenyl)thiazolidin-4-ones (12a-o), modifying chemical structures of previous compounds (3a-o). The modifications are deleting of the CH2CH2 side-chain linker and also in some cases changing the carboxyl group for a tetrazolyl unit and/or the furan ring for pyrrole (Fig. 28).
Fig. 28

Fusion inhibitors of HIV

These modifications resulted in improved activity almost for all compounds. It should be mentioned that two of them, 12-l and 12-m (X-tetrazolyl, Y=O, R=Cl, H and R1=H, F, respectively), showed inhibitory activity against HIV-1IIIB at low nanomolar level (EC50 0.018 ± 0.002 and 0.014 ± 0.005, respectively) and selectivity indexes (SI values) of >2,000. Furthermore, analysis of structure–activity relationships showed that furan derivates were more potent than the pyrroles (12f-i) against HIV-1 IIIB infection (about 40-fold), indicating the favorable role of oxygen at position Y.

Also it was found that tetrazole group in position X is more preferable than COOH group. However, molecular docking studies of active compound with COOH group and with tetrazole revealed that both of them docked in the hydrophobic cavity almost in the same way [164, 187].

Even gp120 protein was recognized as drug target [190, 191] until recently, effective, potent and selective small molecules that act on gp120 were not discovered.

Dezube et al. [192] reported, a bis(disulfonaphthelene) derivative (FP-21399) (Fig. 29) as anti-HIV agent. Unfortunately, despite that it was introduced to phase I clinical studies, its profile in reducing viral load was not good. However, these attempts were continued and led to a molecule 4-methoxy-7-azaindole derivative (BMS-378806), which inhibits infection by HIV-1 strains at nanomolar level [190]. Although the clinical development of this molecule was terminated, a second-generation analogue BMS-488043 replaced the BMS-378806 which showed promising oral bioavailability and safety profile.

4.4.1 Side Effects of Fusion Inhibitors

Among the minor adverse effects of fusion inhibitors are pain, erythema, nodules, or cysts at the site of injection. Other adverse effects may include headache, dizziness, pain or tenderness around the eyes, cough and shortness of breath, loss of appetite and weight loss, and pain in the arms, legs, hands, or feet. Severe adverse effects may include allergic reactions fever, vomiting, kidney problems, low blood pressure, and paralysis.

4.5 Novel Drug Targets: TAR, Tat-Binding Drugs

It is known that the regulatory proteins Tat and Rev are important for HIV replication. The protein Tat (trans-activator of transcription) binds to trans-activator responsive region (TAR) of HIV RNA, stimulating the transcription [170, 193]. An arginine-rich area of Tat recognizes the base sequence and the conformation of TAR RNA. Two kinds of inhibitors targeted the Tat–TAR interaction. The first binds directly to TAR RNA, while, the second binds to the Tat protein. Both of them block the formation of Tat–TAR complex [194, 195].

According to Aboul-Ela et al. [196], small molecules may be able to lock the RNA structure into a conformation that does not allow binding of the Tat protein. The antibiotics neamin and neomycin and their derivatives are representatives of Tat–TAR interaction blockers and may also prevent secondary infections in HIV patients [197, 198].

Furthermore, purine nucleoside analogs such as 5,6-dichloro-1-b-d-ribofuranosylbenzimidazole [199] and carbocyclic adenosine analogs [200, 201] inhibit the Tat action.

On the other hand, Rev protein, which recognizes the Rev-response element (RRE) [202], could be also a potential target for anti-HIV therapy.

5 HAART and Combined Formulations

Currently, the most effective treatment of HIV/AIDS patients is highly active antiretroviral therapy (HAART), which results in sustained reductions in viral load and increases in CD4 cell counts [203, 204].

It includes three or more anti-HIV drugs in combination. First-line regimens at the current time consist of two nucleoside or nucleotide reverse transcriptase inhibitors with a non-nucleoside reverse transcriptase inhibitor, protease inhibitor, or integrase inhibitor [205]. However, most patients continued to have low levels of HIV-1 detectable in the blood using assays that can measure as little as one copy per mL [206].

Initially, several antiretroviral drugs were combined as separate dosage forms; later, to reduce the pill burden and increase patient compliance, such medicines were developed and launched as the combined formulations. Such combination products are listed below.

Drug

Mechanism of action

Company

Year

Lamivudine/zidovudine (Combivir)

Prodrug: active metabolites of lamivudine are lamivudine triphosphate (3TC-TP) and zidovudine triphosphate (ZDV-TP); both are RT inhibitors. 3TC-TP is also a weak inhibitor of the cellular DNA polymerases alpha, beta, and gamma, while ZDV-TP is a weak inhibitor of only the alpha and gamma subtypes

GlaxoSmithKline

1997

Lamivudine/zidovudine/abacavir sulfate (Trizivir)

Triple synthetic nucleoside analogue combination therapy. Prodrugs, active metabolites of lamivudine, zidovudine, and abacavir sulfate are 3TC-TP, ZDV-TP, and carbovir triphosphate (CBV-TP), respectively. 3TC-TP and CBV-TP are also weak inhibitors of the cellular DNA polymerases alpha, beta, and gamma, while ZDV-TP is a weak inhibitor of only the alpha and gamma subtypes

GlaxoSmithKline

2000

Lopinavir/ritonavir (Kaletra)

Lopinavir is an inhibitor of the HIV protease; ritonavir inhibits the CYP3A-mediated metabolism of lopinavir that increases plasma levels of lopinavir

AbbVie

2000

Abacavir sulfate/lamivudine (Epzicom)

Combination product containing two synthetic nucleoside analogs acting as RT inhibitors

GlaxoSmithKline

2004

Tenofovir disoproxil fumarate/emtricitabine (Truvada)

Combination of two nucleoside reverse transcriptase inhibitors (NRTIs). Tenofovir diphosphate is also weak inhibitor of mammalian DNA polymerases alpha, beta, and mitochondrial DNA polymerase gamma, while emtricitabine is a weak inhibitor of mammalian DNA polymerase alpha, beta, epsilon, and mitochondrial DNA polymerase gamma

Gilead

2004

Tenofovir disoproxil fumarate/emtricitabine/efavirenz (Atripla)

Atripla(TM) is a combination of Bristol-Myers Squibb’s non-nucleoside reverse transcriptase inhibitor (NNRTI), Sustiva(R) (efavirenz), and Gilead Science’s Truvada(TM), itself a combination of two nucleoside transcriptase inhibitors (NRTI): emtricitabine and tenofovir disoproxil fumarate

Bristol-Myers Squibb/Gilead

2006

Tenofovir disoproxil fumarate/emtricitabine/rilpivirine hydrochloride (Complera)

Combination of Truvada(R) (tenofovir disoproxil fumarate/emtricitabine) and TMC-278 (rilpivirine hydrochloride), non-nucleoside reverse transcriptase inhibitors

Gilead

2011

Elvitegravir/GS-9350/Truvada (Stribild)

Combination of elvitegravir, GS-9350, tenofovir disoproxil fumarate, and emtricitabine, which jointly act as RT inhibitors, integrase (IN) inhibitors, DNA polymerase inhibitors, and cytochrome P450 CYP3A4 inhibitors

Gilead

2012

Darunavir/cobicistat (Prezcobix)

Combination of darunavir, a HIV protease inhibitor, and cobicistat, a cytochrome P450 CYP3A4 inhibitor

Janssen

2014

Dolutegravir/abacavir/lamivudine (Triumeq)

Combination of RT inhibitors and HIV IN inhibitors

ViiV Healthcare

2014

Atazanavir sulfate/cobicistat (Evotaz)

Combination of HIV protease inhibitors and cytochrome P450 CYP3A4 and CYP2D6 inhibitors

Bristol-Myers Squibb

2015

6 Current Anti-HIV/AIDS Agent Pipeline

Despite the availability of HAART therapy, the further research and development of new anti-HIV agents is needed due to the non-sufficient efficacy of the existing drugs as well as because of severe side effects and arising resistance to the present therapy. Representative examples of novel small molecule drugs and biologics under development are listed below.

Name

Structural formulae

Mechanism of action

Company

Stage

Raltegravir potassium/lamivudine

RT inhibitors/IN inhibitors

Merck & Co.

Registered

Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine

RT inhibitors/IN inhibitors/CYP3A4 inhibitors

Gilead

Preregistered

Emtricitabine/rilpivirine hydrochloride/tenofovir alafenamide fumarate

RT inhibitors

Gilead

Preregistered

Emtricitabine/tenofovir alafenamide fumarate

RT inhibitors

Gilead

Preregistered

HIV-1 immunogen (Remune)

HIV vaccine candidate

Immune Response BioPharma

Preregistered

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide fumarate

RT inhibitors/protease inhibitors/CYP3A4 inhibitors

Gilead

Phase III

Dolutegravir/rilpivirine

RT inhibitors/IN inhibitors/

ViiV Healthcare/Janssen

Phase III

AIDSVAX gp120 B/E

Bivalent vaccine candidate

Walter Reed Army Institute

Phase III

ALVAC E120TMG

 

Walter Reed Army Institute/Sanofi Pasteur

Phase III

Albuvirtide

Polypeptide

HIV fusion inhibitors

Frontier Biotechnologies

Phase III

Apricitabine

Open image in new window

RT inhibitors

Avexa

Phase III

Dapivirine

Open image in new window

RT inhibitors

International Partnership Microbicides

Phase III

Doravirine

Open image in new window

RT inhibitors/IN inhibitors/CYP3A4 inhibitors

Merck & Co.

Phase III

Fostemsavir

Open image in new window

HIV attachment inhibitors/CYP3A4 inhibitors

Bristol-Myers Squibb

Phase III

MK-1439A

RT inhibitors/IN inhibitors/DNA polymerase inhibitors/CYP3A4 inhibitors

Merck & Co.

Phase III

PRO-140

Humanized monoclonal IgG4 kappa antibody

Anti-CD195 (CCR5)/signal transduction modulators/viral entry inhibitors

CytoDyn

Phase III

S-247303

IN inhibitors

ViiV Healthcare

Phase III

Tubercin T-5

Carbohydrate complex, a mixture of low molecular-weight polysaccharides with arabinomannan structure extracted from Mycobacterium tuberculosis

Artec

Phase III

Alpha1-Antitrypsin (human)

Biological source-derived proteins

 

Grifols

Phase II/III

4E10/2F5/2G12

Combination of the anti-HIV-1 human monoclonal antibodies 4E10, 2F5, and 2G12

Viral entry inhibitors

Polymun

Phase II

ABX-464

Open image in new window

HIV replication inhibitors

Abivax

Phase II

AGS-004

AIDS vaccine consisting of dendritic cells electroporated with autologous amplified HIV-1 gag, nef, rev, and vpr RNA antigens and CD40 ligand RNA

 

Argos Therapeutics

Phase II

BIT-225

Open image in new window

Nucleocapsid p7 protein (NCp7) zinc finger inhibitors

Biotron Ltd.

Phase II

BMS-955176

 

Bristol-Myers Squibb

Phase II

C7-DHAdC

Oral prodrug of KP-1212-triphosphate, the active RT metabolite and substrate

 

Koronis

Phase II

Cabotegravir

Open image in new window

IN inhibitors

ViiV Healthcare

Phase II

Cenicriviroc mesylate

Open image in new window

HIV attachment inhibitors/chemokine CCR5 antagonists/chemokine CCR2B receptor ligands/signal transduction modulators

Tobira Therapeutics

Phase II

Censavudine

Open image in new window

RT inhibitors

Oncolys

Phase II

Chloroquine phosphate

Open image in new window

Apoptosis inducers

NIAID

Phase II

FIT-06

AIDS vaccine consisting of a DNA plasmid expressing HIV-1 B-clade nef, rev, tat, gag, pol, env, and CTL epitopes

 

FIT Biotech

Phase II

GS-9883

IN inhibitors

Gilead

Phase II

GTU-MultiHIV multiclade

DNA-based HIV vaccine candidate

 

FIT Biotech

Phase II

HIV-LIPO-5

AIDS vaccine candidate that contains five lipopeptides from gag, nef, and pol corresponding to more than 50 epitopes

 

ANRS

Phase II

Hydroxychloroquine sulfate

Open image in new window

Autophagy inhibitors

Medical Research Council (MRC)

Phase II

IR-103

Open image in new window

TLR9 receptor agonists/signal transduction modulators

Immune Response BioPharma

Phase II

ITV-1

AIDS vaccine consisting of an inactivated purified extract of porcine pepsin recognizing HIV gp41 and gp120 proteins

 

Immunotech Laboratories

Phase II

Ibalizumab

Immunoglobulin G4, anti-(human CD4 (antigen)) (human–mouse monoclonal 5A8 gamma4-chain), disulfide with human–mouse monoclonal 5A8 kappa-chain, dimer

HIV attachment inhibitors/anti-CD4

TaiMed Biologics

Phase II

LC-002

DNA vaccine

 

Genetic Immunity

Phase II

Lersivirine

Open image in new window

RT inhibitors

ViiV Healthcare

Phase II

Lexgenleucel-T

Lentiviral vector expressing an antisense sequence targeted to the HIV-1 envelope (env) gene

env expression inhibitors

VIRxSYS

Phase II

MVA-62B (GOVX-B11)

Modified vaccinia Ankara vector containing HIV-1 gag, pr, rt, and env genes from clade B

Recombinant vector vaccines

GeoVax Labs/NIAID

Phase II

PF-232798

HIV attachment inhibitors/chemokine CCR5 antagonists/signal transduction modulators

ViiV Healthcare

Phase II

Rintatolimod

5′-Inosinic acid homopolymer, complex with 5′-cytidylic acid polymer with 5′-uridylic acid (1:1)

TLR3 receptor agonists/signal transduction modulators

HemispheRx

Phase II

SB-728-T

Autologous CD4+ cells genetically modified at the CCR5 gene by zinc finger nucleases

CCR5 expression inhibitors

Sangamo

Phase II

Sevelamer carbonate

Epichlorohydrin-cross-linked polyallylamine carbonate

 

NIAID

Phase II

Sifuvirtide

Polypeptide

HIV fusion inhibitors

FusoGen Pharmaceuticals

Phase II

TMC-310911

Open image in new window

HIV protease inhibitors

Janssen R&D Ireland

Phase II

UB-421

Anti-CD4 monoclonal antibody

Anti-CD4

United Biomedical

Phase II

VAC-3S

Peptide vaccines

 

InnaVirVax

Phase II

VM-1500

 

RT inhibitors

Viriom

Phase II

VRC-HIVADV014-00-VP

The vaccine candidate is composed of four adenoviral vectors (in a 3:1:1:1 ratio) that encode the HIV-1 Gag/Pol polyprotein from clade B and HIV-1 Env glycoproteins from clades A, B, and C

 

NIAID

Phase II

VRC-HIVDNA016-00-VP

Multivalent HIV-1 DNA vaccine

 

NIAID

Phase II

Vacc-4x

HIV vaccine consisting of four water-soluble synthetic HIV-1 core protein (p24)-like modified consensus peptides (Vac-10, −11, −12 and −13)

 

Bionor Pharma

Phase II

Vorinostat

Open image in new window

Histone deacetylase 1 (HDAC1) inhibitors/apoptosis inducers/histone deacetylase 2 (HDAC2) inhibitors/histone deacetylase 3 (HDAC3) inhibitors/histone deacetylase 6 (HDAC6) inhibitors

Merck & Co.

Phase II

pGA2/JS7 (GOVX-B11)

DNA plasmid containing gag, pro, RT, env, tat, rev, and vpu genes from HIV-1 clade B

 

GeoVax Labs/NIAID

Phase II

rTat (IIIB-BH-10)

Recombinant HIV-1 (HTLV-IIIB strain, clone BH-10) Tat protein-based vaccine

 

Istituto Superiore di Sanita

Phase II

791760

HIV clade B′/C DNA vaccine

 

Chinese Center Disease Control Prevent

Phase II

According to the data presented in Thomson Reuters Integrity database (http://integrity.thomson-pharma.com), there are about 100 other anti-HIV/AIDS agents at earlier stages of clinical trials or in preclinical studies. The distribution of all anti-HIV/AIDS agents versus different stages of R & D is given in Fig. 29.

As one may see from the data presented in Fig. 29, only one anti-HIV agent was already withdrawn from the market. It was amprenavir, HIV-1 protease inhibitor, that was launched in 1999 under a collaboration agreement between GlaxoSmithKline, Kissei Pharmaceutical, and Vertex for the oral treatment of HIV infection in combination with other antiretrovirals in children 4 years of age and older and in adults. Amprenavir works by binding to the active site of HIV-1 protease, thereby, preventing the processing of viral gag and gag–pol polyprotein precursors. This results in the formation of immature and noninfectious virions. In 2005, Kissei Pharmaceutical issued a decision to voluntarily withdraw the marketing authorization for the product in Japan. Marketing authorization in the EU was withdrawn in 2010.
Fig. 29

The number of current anti-HIV/AIDS agents at different stages of research and development

Distribution of all anti-HIV/AIDS agents versus different molecular targets is given in Fig. 30. As one may see from this data, the most popular targets now are: HIV integrase = HIV pol = HIV-1 nucleocapsid protein p7 = HIV-1 protease > reverse transcriptase > HIV gag > HIV env > chemokine CCR5 receptor, etc. Fifteen compounds are CYP3A4 inhibitors, which act in combination with anti-HIV agents increasing their concentration in plasma.
Fig. 30

The number of anti-HIV/AIDS agent with different targets

7 The Future Trends

As one may see from the presented above overview of the current status of the anti-HIV agents development, nowadays antiretroviral therapy is able to decrease significantly the mortality of HIV-infected people in industrially developed countries. However, the existing antiretroviral therapy is still too expensive for patients living in low-income and middle-income countries [207, 208]. Moreover, the available antiretroviral drugs do not lead to complete curation of HIV infection, cause severe adverse effect, and lead to the appearance of resistant strains. Thus, the discovery of the novel more safety and efficacious anti-HIV medicines still remains the essential challenge.

7.1 Attempts to Overcome the Latent HIV Infection

One of the problems that prevent the complete curation of HIV-1 infection is the persistence of a viral reservoir that harbors integrated provirus within host-cellular DNA. This latent infection is unaffected by antiretroviral therapy and unseen by the immune system. To solve this problem, the mechanisms of latent infection and the sources of viral reservoirs are studied in detail now [207, 209]. Recent achievements in understanding of the latent reservoirs and new approaches to eradicate established HIV-1 infection and avoid the burden of lifelong ART are reviewed in several publications [209, 210]. In particular, one established mechanism of the patent HIV infection is associated with the repression of chromatin on the HIV-1 promoter. Histone deacetylation is a key modification connected with transcriptional repression of the HIV-1 promoter, and inhibition of histone deacetylase (HDAC) enzymes reactivates the latent HIV-1. Therapeutic potential in reactivating the latent HIV-1 by different HDAC inhibitors is discussed [211, 212, 213, 214].

7.2 Natural Products as Potential Anti-HIV Agents

Natural products are known as the primary source of over 50 % of currently existing drugs [215]. It was demonstrated that they provide higher chemical diversity in comparison with the libraries of organic synthetic molecules [216]. Due to that, screening of plant extracts and other libraries of natural products is widely used for discovery of new anti-HIV agents [216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233] (http://www.ibscreen.com). We predicted the biological activities associated with the molecular mechanisms of anti-HIV action using computer program PASS (Prediction of Activity Spectra for Substances) [234] (http://www.way2drug.com/passonline) for the library of over 56,000 natural compounds, their analogs, and derivatives provided by InterBioScreen Ltd. (http://www.ibscreen.com). As one may see from the Fig. 31, this library is rather promising for screening of novel anti-HIV agents.
Fig. 31

Anti-HIV mechanisms of action predicted by PASS of InterBioScreen library of natural compounds (cutoff Pa>Pi, where Pa is the probability to be active, Pi is the probability to be inactive)

7.3 Biologicals as Potential Anti-HIV Agents

In addition to the small molecules of natural or synthetic origin, which are presently studied as novel anti-HIV agents, the large number of biological products is investigated. According to the Thomson Reuters Integrity (http://integrity.thomson-pharma.com), over 100 biologicals are studied as anti-HIV medicines. Their distribution by product categories is shown in Fig. 32. As one may see from the data presented here, the most actively studied are HIV vaccines > recombinant vector vaccines > DNA vaccines > polypeptides, from 41 AA > peptide vaccines > dendritic cell vaccines, etc. Also, among the different studied approaches to anti-HIV therapy, one finds the gene therapy, antisense therapy, short hairpin RNA (shRNA), and oligoribonucleotide (RNA). Gene-based therapies that utilize RNA interference (RNAi) to silence the expression of viral or host mRNA targets that are required for HIV-1 infection and/or replication are reviewed recently [225].
Fig. 32

Products categories of biologics under R & D as anti-HIV medicines

It was shown that HIV-1 infectivity is influenced by the host-cellular miRNAs, and current results in the field of miRNA and HIV-1 interplay were recently discussed [226]. Didigu C and Doms R. considered the effects of gene therapy targeting HIV entry and impacts of allogeneic stem cell transplantation in the development of strategies to cure HIV infection [208]. Also, DNA aptamers to the HIV-1 reverse transcriptase are studied as potential therapeutic agents for treatment of HIV/AIDS [227].

However, till now the only biological product is launched as a remedy for anti-HIV therapy. This is the immune globulin intravenous (IGIV-C) developed as an immunomodulator and launched by Bayer for treatment of HIV infections in 2004 and approved in the USA for the treatment of primary immunodeficiency diseases by Grifols in 2010 (http://integrity.thomson-pharma.com).

7.4 Computer-Aided Drug Discovery of New Anti-HIV Agents

In recent years, computer-aided drug design methods are widely used in research and development of novel pharmacological agents for finding and optimizing hits and lead compounds [228, 229]. The basic computational methods include molecular docking, pharmacophore search, and (Q)SAR modeling. Since the field of anti-HIV drug discovery is extensively studied, both target-based and ligand-based drug design methods could be applied. Some examples of fresh works in this direction are given below.

Recently, novel HIV-1 protease inhibitors were identified by virtual screening using a complementary set of computational methods [230]. The potential HIV-1 protease inhibitors were searched in the National Cancer Institute (NCI) database, which contains 260,000 structures of organic compounds. Six molecules were selected based on computational prediction, and two of them (NSC111887 and NSC121217) showed inhibitory potency against HIV-1 protease in vitro, with IC50 values of 62 and 162 μM, respectively. The authors concluded that these compounds could be used for the further optimization as HIV-1 protease inhibitors.

Extract of Caesalpinia sappan L. was found to exhibit HIV-1 integrase inhibiting activity [231]. Nine compounds were extracted from the heartwoods and roots of C. sappan L. The most potent compounds against HIV-1 IN were sappanchalcone and protosappanin A with IC50 values 2.3 and 12.6 μM, respectively. Using molecular docking, the authors determined that these compounds presumably bind to the amino acid residues Gln148 and Thr66 in the core domain of HIV-1 integrase.

A few derivatives of N-substituted benzyl/phenyl-2-(3,4-dimethyl-5,5-dioxidopyrazolo[4,3-c][1,2]benzothiazin-2(4H)-yl)acetamides were found to exhibit the anti-HIV activity with IC50 < 20 μM [232]. Then, using molecular docking to the RT-bound nevirapine X-ray data, the authors determined that the presumable molecular mechanism of these compounds is binding in the NNRTI pocket of the HIV-1 reverse transcriptase.

Potential HIV-1 reverse transcriptase inhibitors were designed in silico as N-heteroaryl compounds bearing pyrimidine and benzimidazole moieties [233]. The designed compounds were synthesized and tested in cell assays using laboratory-adapted strains HIV-1IIIB (X4, subtype B) and HIV-1Ada5 (R5, subtype B) and the primary isolates HIV-1UG070 (X4, subtype D) and HIV-1VB59 (R5, subtype C). It was shown that the compounds were active at IC50 1.4 μM with the selectivity index ranged from 1.29 to 38.39.

Structural details regarding the interactions between the inhibitors and CXCR4 were determined using holographic QSAR, docking, and molecular dynamics studies [235]. It was found that the binding is affected by two crucial residues Asp97 and Glu288. Structure–activity relationships were analyzed, and the obtained results will be useful for rational design of novel CXCR4 inhibitors.

Molecular modeling and site-directed mutagenesis studies on the RNase H domain demonstrated different binding poses for ester and acid diketo acids. It was shown that they interact with residues (Arg448, Asn474, Gln475, Tyr501, and Arg557) involved not in the catalytic motif but in highly conserved portions of the RNase H primer grip motif [236]. Therefore, the authors showed that RNase H inhibition by diketo acids is not only due to their chelating properties but also to the specific interactions with highly conserved amino acid residues in the RNase H domain. This finding provides important insights for the rational design of novel RNase H inhibitors.

To overcome the resistance to the available anti-HIV agents, rational design of inhibitors with dual mechanisms of action was performed [237]. Inhibitors of both HIV-1 reverse transcriptase (RT) DNA polymerase (DP) and ribonuclease H (RNase H) were discovered among the small library of 1,3-diarylpropenones, which exhibited dual inhibition properties in the low-micromolar range.

More information about the multi-targeted antiretroviral agents may be found in the paper [238].

Examples of application of in silico methods to the design and discovery of novel anti-HIV agents presented above clearly demonstrated that both target-based and ligand-based methods are useful for optimization of synthesis and biological testing of hits and lead compounds. Earlier [239], using the information from the NCI database about compounds tested in anti-HIV assays, we demonstrated that based on predictions of the computer program PASS [234], it is possible to reduce the number of experiments up to 17 times.

More information about applications of computational methods to the discovery and optimization of novel anti-HIV agents may be found in the papers [240, 241, 242, 243, 244]. Detailed consideration of the dynamics of HIV-1 reverse transcriptase complexes with different ligands and with a number of mutations allowed to reveal a novel mechanism for drug resistance to non-nucleoside RT inhibitors [245]. Computer-aided design of protein–protein interaction inhibitors as agents for potential agents for anti-HIV therapy is described in the paper [19].

Some latest algorithmic and methodological developments for application of docking to design of novel pharmacological agents were recently published [246]. An effective strategy was proposed using three orthogonal metrics for assessment and validation: pose reproduction over a large database of protein–ligand complexes, cross docking to 24 drug-target protein families, and database enrichment using large active and decoy datasets for five proteins including HIV-1 protease.

Since in the past few years the data on structures and biological activity of known anti-HIV agents are collected and presented by several publicly available resources (PubChem (http://pubchem.ncbi.nlm.nih.gov), ChEMBL (http://www.ebi.ac.uk/chembl), ChemSpider (http://www.chemspider.com), DrugBank (http://www.drugbank.ca), etc.), this stimulates the creating of numerous (Q)SAR models and their application to design and discovery of novel candidates for HIV/AIDS treatment. As was recently shown [247], this data could not be used for this purpose “as they are”; instead, the experts’ estimates and careful prefiltering of the available data are necessary to obtain the (Q)SAR models with reasonable accuracy and predictivity.

Moreover, despite the development and application of powerful computational drug design methods, the essential role of researchers’ intuition and serendipity in finding of efficacious antiretroviral drugs is emphasized [248, 249].

References

  1. 1.
    Zhu T, Korber BT, Nahmias AJ, Hooper E, Sharp PM, Ho DD (1998) An African HIV-1 sequence from 1959 and implications for the origin of the epidemic. Nature 391(6667):594–597PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Worobey M, Gemmel M, Teuwen DE, Haselkorn T, Kunstman K, Bunce M, Muyembe JJ, Kabongo JM, Kalengayi RM, Van Marck E, Gilbert MT, Wolinsky SM (2008) Direct evidence of extensive diversity of HIV-1 in Kinshasa by 1960. Nature 455(7213):661–664PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Frøland SS, Jenum P, Lindboe CF, Wefring KW, Linnestad PJ, Böhmer T (1988) HIV-1 infection in Norwegian family before 1970. Lancet 1(8598):1344–1345PubMedCrossRefGoogle Scholar
  4. 4.
    Worobey M, Telfer P, Souquière S, Hunter M, Coleman CA, Metzger MJ, Reed P, Makuwa M, Hearn G, Honarvar S, Roques P, Apetrei C, Kazanji M, Marx PA (2010) Island biogeography reveals the deep history of SIV. Science 329(5998):1487PubMedCrossRefGoogle Scholar
  5. 5.
    Bailes E, Gao F, Bibollet-Ruche F, Courgnaud V, Peeters M, Marx PA, Hahn BH, Sharp PM (2003) Hybrid origin of SIV in chimpanzees. Science 300(5626):1713PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Gao G, Bailes E, Robertson DL, Chen Y, Rodenburg CM, Michael SF, Cummins LB, Arthur LO, Peeters M, Shaw GM, Sharp PM, Hahn BH (1999) Origin of HIV-1 in the chimpanzee Pan troglodytes. Nature 397:436–444PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Lemey P, Pybus OG, Wang B, Saksena NK, Salemi M, Vandamme AM (2003) Tracing the origin and history of the HIV-2 epidemic. Proc Natl Acad Sci 100:6588–6592PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Global report of the Joint United Nations Program for AIDS (UNAIDS) (2013) http://www.unaids.org/sites/default/files/media_asset/UNAIDS_Global_Report_2013_en_1.pdf
  9. 9.
    De Clercq E (2013) The nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors in the treatment of HIV infections (AIDS). Adv Pharmacol 67:317–358PubMedCrossRefGoogle Scholar
  10. 10.
    Flexner C, Saag M (2013) The antiretroviral drug pipeline: prospects and implications for future treatment research. Curr Opin HIV AIDS 8(6):572–578PubMedCrossRefGoogle Scholar
  11. 11.
    McGowan I (2014) An overview of antiretroviral pre-exposure prophylaxis of HIV infection. Am J Reprod Immunol 71(6):624–630PubMedCrossRefGoogle Scholar
  12. 12.
    Assaes CP, Sáez-Cirión A (2014) HIV cure research: advances and prospects. Virology 454–455:340–352Google Scholar
  13. 13.
    De Clercq E (2013) A cutting-edge view on the current state of antiviral drug development. Med Res Rev 33(6):1249–1277PubMedGoogle Scholar
  14. 14.
    Maga G, Veljkovic N, Crespan E, Spadari S, Prljic J, Perovic V, Glisic S, Veljkovic V (2013) New in silico and conventional in vitro approaches to advance HIV drug discovery and design. Expert Opin Drug Discovery 8(1):83–92CrossRefGoogle Scholar
  15. 15.
    Métifiot M, Marchand C, Pommier Y (2013) HIV integrase inhibitors: 20-year landmark and challenges. Adv Pharmacol 67:75–105PubMedCrossRefGoogle Scholar
  16. 16.
    Yu F, Lu L, Du L, Zhu X, Debnath AK, Jiang S (2013) Approaches for identification of HIV-1 entry inhibitors targeting gp41 pocket. Viruses 5(1):127–149PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Lagunin AA, Filimonov DA, Gloriozova TA, Tarasova OA, Zakharov AV, Guasch L, Nicklaus MC, Poroikov VV (2013) Virtual screening for potential substances for the prophylaxis of HIV infection in libraries of commercially available organic compounds. Pharm Chem J 47(7):343–360CrossRefGoogle Scholar
  18. 18.
    Lange JM, Ananworanich J (2014) The discovery and development of antiretroviral agents. Antivir Ther 19(Suppl 3):5–14PubMedCrossRefGoogle Scholar
  19. 19.
    Veselovsky AV, Zharkova MS, Poroikov VV, Nicklaus MC (2014) Computer-aided design and discovery of protein-protein interaction inhibitors as agents for anti-HIV therapy. SAR QSAR Environ Res 25(6):457–471PubMedCrossRefGoogle Scholar
  20. 20.
    Di Santo R (2014) Inhibiting the HIV integration process: past, present, and the future. J Med Chem 57(3):539–566. Erratum in: J Med Chem. 2014 Jul 24; 57(14):6273Google Scholar
  21. 21.
    Tintori C, Brai A, Fallacara AL, Fazi R, Schenone S, Botta M (2014) Protein-protein interactions and human cellular cofactors as new targets for HIV therapy. Curr Opin Pharmacol 18:1–8PubMedCrossRefGoogle Scholar
  22. 22.
    Han YS, Xiao WL, Xu H, Kramer VG, Quan Y, Mesplède T, Oliveira M, Colby-Germinario SP, Sun HD, Wainberg MA (2015) Identification of a dibenzocyclooctadiene lignan as a HIV-1 non-nucleoside reverse transcriptase inhibitor. Antivir Chem Chemother 24(1):28–38PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Patel RV, Park SW (2015) Pyrroloaryls and pyrroloheteroaryls: inhibitors of the HIV fusion/attachment, reverse transcriptase and integrase. Bioorg Med Chem pii: S0968-0896(15)00510-6. doi: 10.1016/j.bmc.2015.06.016. [Epub ahead of print] Review. PubMedCrossRefGoogle Scholar
  24. 24.
    Chiu IM, Yaniv A, Dahlberg JE, Gazit A, Skuntz SF, Tronick SR, Aaronson SA (1985) Nucleotide sequence evidence for relationship of AIDS retrovirus to lentiviruses. Nature 317(6035):366–3688PubMedCrossRefGoogle Scholar
  25. 25.
    Wain-Hobson S, Alizon M, Montagnier L (1985) Relationship of AIDS to other retroviruses. Nature 313(6005):743PubMedCrossRefGoogle Scholar
  26. 26.
    Vogt PK (1997) Historical introduction to the general properties of retroviruses. In: Coffin JM, Hughes SH, Varmus HE (eds) Retroviruses. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp 1–27Google Scholar
  27. 27.
    Weiss RA (1993) Cellular receptors and viral glycoproteins involved in retrovirus entry. In: Levy JA (ed) The retroviridae, vol 2. Plenum, New York, pp 1–108Google Scholar
  28. 28.
    Miceli MC, Parnes JR (1993) Role of CD4 and CD8 in T cell activation and differentiation. Adv Immunol 53:59–122PubMedCrossRefGoogle Scholar
  29. 29.
    Choe H, Farzan M, Sun Y, Sullivan N, Rollins B, Ponath PD, Wu L, Mackay CR, LaRosa G, Newman W, Gerard N, Gerard C, Sodroski J (1996) The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 85(7):1135–1148PubMedCrossRefGoogle Scholar
  30. 30.
    Deng H, Liu R, Ellmeier W, Choe S, Unutmaz D, Burkhart M, Di Marzio P, Marmon S, Sutton RE, Hill CM, Davis CB, Peiper SC, Schall TJ, Littman DR, Landau NR (1996) Identification of a major co-receptor for primary isolates of HIV-1. Nature 381(6584):661–6666PubMedCrossRefGoogle Scholar
  31. 31.
    Doranz BJ, Rucker J, Yi Y, Smyth RJ, Samson M, Peiper SC, Parmentier M, Collman RG, Doms RW (1996) A dual-tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors. Cell 85(7):1149–1158PubMedCrossRefGoogle Scholar
  32. 32.
    Hoffman TL, Stephens EB, Narayan O, Doms RW (1998) HIV type I envelope determinants for use of the CCR2b, CCR3, STRL33, and APJ coreceptors. Proc Natl Acad Sci U S A 95(19):11360–11365PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Scholten DJ, Canals M, Maussang D, Roumen L, Smit MJ, Wijtmans M, de Graaf C, Vischer HF, Leurs R (2012) Pharmacological modulation of chemokine receptor function. Br J Pharmacol 165(6):1617–1643PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Zhang L, He T, Huang Y, Chen Z, Guo Y, Wu S, Kunstman KJ, Brown RC, Phair JP, Neumann AU, Ho DD, Wolinsky SM (1998) Chemokine co-receptor usage by diverse primary isolates of human immunodeficiency virus type 1. J Virol 72(11):9307–9312PubMedPubMedCentralGoogle Scholar
  35. 35.
    Eckert DM, Kim PS (2001) Mechanisms of viral membrane fusion and its inhibition. Annu Rev Biochem 70:777–810PubMedCrossRefGoogle Scholar
  36. 36.
    Chun TW, Carruth L, Finzi D, Shen X, Di Giuseppe JA, Taylor H, Hermankova M, Chadwick K, Margolick J, Quinn TC, Kuo YH, Brookmeyer R, Zeiger MA, Barditch-Crovo P, Siliciano RF (1997) Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 387:183–188PubMedCrossRefGoogle Scholar
  37. 37.
    Whittle H, Morris J, Todd J, Corrah T, Sabally S, Bangali J, Ngom PT, Rolfe M, Wilkins A (1994) HIV-2-infected patients survive longer than HIV-1-infected patients. AIDS 8:1617–1620PubMedCrossRefGoogle Scholar
  38. 38.
    Divita G, Rittinger K, Geourjon C, Deleage G, Goody RS (1995) Dimerization kinetics of HIV-1 and HIV-2 reverse transcriptase: a two step process. J Mol Biol 245:508–521PubMedCrossRefGoogle Scholar
  39. 39.
    Barat C, Lullien V, Schatz O, Keith G, Nugeyre MT, Gruninger-Leitch F, Barre-Sinoussi F, Grice L, Darlix JL (1989) HIV-1 reverse transcriptase specifically interacts with the anticodon domain of its cognate primer tRNA. EMBO J 8(32):3279–3285PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Sarih-Cottin L, Bordier B, Musier-Forsyth K, Andreola M-L, Barr PJ, Litvak S (1992) Preferential interaction of HIV RT with two regions of primer tRNALys3 as evidenced by footprinting studies and inhibition with synthetic oligoribonudeotides. J Mol Biol 226:1–6PubMedCrossRefGoogle Scholar
  41. 41.
    Litvak LE, Andderola M-L, Nevinsky GA, Sarih-Cofttin L, Litvax S (1994) The reverse transcriptase of HIV-1: from enzyrnology to therapeutic intervention Laboratoire de Replication et Expression des Genomes eucaryotes et Retroviraux, institut Biochimie Cellulaire, CNRS5 33077 Bordeaux cedex, France, vol 8. pp 497–502.8Google Scholar
  42. 42.
    Tu X, Das K, Han Q, Bauman JD, Clark AD, Hou X, Frenkel YV, Gaffney BL, Jones RA, Boyer PL, Hughes SH, Sarafianos SG, Arnold E (2010) Structural basis of HIV-1 resistance to AZT by excision. Nat Struct Mol Biol 17:1202PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Madej T, Lanczycki CJ, Zhang D, Thiessen PA, Geer RC, Marchler-Bauer A, Bryant SH (2014) MMDB and VAST+: tracking structural similarities between macromolecular complexes. Nucleic Acids Res 42(Database issue):D297–D303PubMedCrossRefGoogle Scholar
  44. 44.
    Kohlstaedt LA, Wang J, Friedman JM, Rice PA, Steitz TA (1992) Crystal structure at 3.5 A resolution of HIV-1 RT complexed with an inhibitor. Science 256:1783–1790PubMedCrossRefGoogle Scholar
  45. 45.
    Huang H, Chopra R, Verdine GL, Harrison SC (1998) Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance. Science 28:1669–1675CrossRefGoogle Scholar
  46. 46.
    Arts EJ, Wainberg MA (1996) Mechanisms of nucleoside analog antiviral activity and resistance during human immunodeficiency virus reverse transcription. Antimicrob Agents Chemother 40:527–540PubMedPubMedCentralGoogle Scholar
  47. 47.
    Squires KE (2001) An introduction to nucleoside and nucleotide analogues. Antivir Ther 6(Suppl 3):1–14PubMedGoogle Scholar
  48. 48.
    Prasad VR, Goff SP (1990) Structure-function studies of HIV reverse transcriptase. Ann N Y Acad Sci 616:11–21PubMedCrossRefGoogle Scholar
  49. 49.
    St Clair MH, Richards CA, Spector T et al (1987) 3′-Azido-3′-deoxythymidine triphosphate as an inhibitor and substrate of purified human immunodeficiency virus reverse transcriptase. Antimicrob Agents Chemother 31:1972–1977PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Lewis W, Gonzalez B, Chomyn A, Papoian T (1992) Zidovudine induces molecular, biochemical, and ultrastructural changes in rat skeletal muscle mitochondria. J Clin Invest 89:1354–1360PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Lewis W, Dalakas MC (1995) Mitochondrial toxicity of antiviral drugs. Nat Med 1:417–422PubMedCrossRefGoogle Scholar
  52. 52.
    Schambelan M, Benson CA, Carr A, Currier JS, Dube P, Gerber JG, Grinspoon SK, Saag MS (2002) Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of an International AIDS Society-USA panel. J Acquir Immune Defic Syndr 31:257–275PubMedCrossRefGoogle Scholar
  53. 53.
    Falco V, Rodriguez D, Ribera E, Martinez E, Miro JM, Domingo P, Diazaraque R, Jose RA, Gonzalez-Garcia JJ, Montero F, Sanchezl L, Pathissa A (2002) Severe nucleoside-associated lactic acidosis in human immunodeficiency virus-infected patients: report of 12 cases and review of the literature. Clin Infect Dis 34:838–846PubMedCrossRefGoogle Scholar
  54. 54.
    Miller KD, Cameron M, Wood LV, Dalakas MC, Kovacs JA (2000) Lactic acidosis and hepatic steatosis associated with use of stavudine: report of four cases. Ann Intern Med 133:192–196PubMedCrossRefGoogle Scholar
  55. 55.
    Bissuel F, Bruneel F, Habersetzer F et al (1994) Fulminant hepatitis with severe lactate acidosis in HIV-infected patients on didanosine therapy. J Intern Med 235:367–371PubMedCrossRefGoogle Scholar
  56. 56.
    Chattha G, Arieff AI, Cummings C, Tierney LM Jr (1993) Lactic acidosis complicating the acquired immunodeficiency syndrome. Ann Intern Med 118:37–39PubMedCrossRefGoogle Scholar
  57. 57.
    Smerdon SJ, Jager J, Wang J, Kohlstaedt LA, Chirino AJ, Friedman JM, Rice PA, Steitz TA (1994) Structure of the binding site for nonnucleoside inhibitors of the reverse transcriptase of human immunodeficiency virus type 1. Proc Natl Acad Sci U S A 91(9):3911–3915PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Pitta E, Crespan E, Geronikaki A, Maga G, Samuele A (2010) Novel thiazolidinone derivatives with an uncommon mechanism of inhibition towards HIV-1 reverse transcriptase. Lett Drug Des Discovery 7(4):228–234CrossRefGoogle Scholar
  59. 59.
    Das K, Lewi PJ, Hughes SH, Arnold E (2005) Crystallography and the design of anti-AIDS drugs: conformational flexibility and positional adaptability are important in the design of non-nucleoside HIV-1 reverse transcriptase inhibitors. Prog Biophys Mol Biol 88:209–231PubMedCrossRefGoogle Scholar
  60. 60.
    Hsiou Y, Das K, Ding J, Clark AD Jr, Kleim JP, Rosner M, Winkler I, Riess G, Hughes SH, Arnold E (1998) Structures of Tyr188Leu mutant and wild-type HIV-1 reverse transcriptase complexed with the non-nucleoside inhibitor HBY 097: inhibitor flexibility is a useful design feature for reducing drug resistance. J Mol Biol 284(2):313–323PubMedCrossRefGoogle Scholar
  61. 61.
    Das K, Clark AD Jr, Lewi PJ, Heeres J, De Jonge MR, Koymans LM, Vinkers HM, Daeyaert F, Ludovici DW, Kukla MJ, De Corte B, Kavash RW, Ho CY, Ye H, Lichtenstein MA, Andries K, Pauwels R, De Bethune MP, Boyer PL, Clark P, Hughes SH, Janssen PA, Arnold E (2004) Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related nonnucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug resistant HIV-1 variants. J Med Chem 47(10):2550–2560PubMedCrossRefGoogle Scholar
  62. 62.
    Janssen PA, Lewi PJ, Arnold E, Daeyaert F, de Jonge M, Heeres J, Koymans L, Vinkers M, Guillemont J, Pasquier E, Kukla M, Ludovici D, Andries K, de Bethune MP, Pauwels R, Das K, Clark AD Jr, Frenkel YV, Hughes SH, Medaer B, De Knaep F, Bohets H, De Clerck F, Lampo A, Williams P, Stoffels P (2005) In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]-amino]benzonitrile (R278474, rilpivirine). J Med Chem 48(6):1901–1909PubMedCrossRefGoogle Scholar
  63. 63.
    Ren J, Milton J, Weaver KL, Short SA, Stuart DI, Stammers DK (2000) Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase. Struct Fold Des 8:1089CrossRefGoogle Scholar
  64. 64.
    Ren J, Nichols CE, Chamberlain PP, Weaver KL, Short SA, Stammers DK (2004) Crystal structures of HIV-1 reverse transcriptases mutated at codons 100, 106 and 108 and mechanisms of resistance to non-nucleoside inhibitors. J Mol Biol 336:569–579PubMedCrossRefGoogle Scholar
  65. 65.
    Monforte AM, Logoteta P, Ferro S, De Luca L, Iraci N, Maga G, Clercq ED, Pannecouque C, Chimirri A (2009) Design, synthesis, and structure-activity relationships of 1,3-dihydrobenzimidazol-2-one analogues as anti-HIV agents. Bioorg Med Chem 17(16):5962–5967PubMedCrossRefGoogle Scholar
  66. 66.
    Pauwels R, Andries K, Debyser Z, Van Daele P, Schols D, Stoffels P, De Vreese K, Woestenborghs R, Vandamme AM, Janssen CG (1993) Potent and highly selective human immunodeficiency virus type 1 (HIV-1) inhibition by a series of alpha-anilinophenylacetamide derivatives targeted at HIV-1 reverse transcriptase. Proc Natl Acad Sci U S A 90(5):1711–1715PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Balzarini J, Orzeszko-Krzesińska B, Maurin JK, Orzeszko A (2009) Synthesis and anti-HIV studies of 2-and 3-adamantyl-substituted thiazolidin-4-ones. Eur J Med Chem 44:303–311PubMedCrossRefGoogle Scholar
  68. 68.
    Pauwels R, Andries K, Desmyter J, Schols D, Kukla MJ, Breslin HJ, Raeymaeckers A, Van Gelder J, Woestenborghs R, Heykants J, Schellekens K, Janssen M, De Clerq E, Janssen PAJ (1990) Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives. Nature 343(6257):470–474PubMedCrossRefGoogle Scholar
  69. 69.
    Althaus IW, Chou JJ, Gonzales AJ, Deibel MR, Chou KC, Kezdy FJ, Romero DL, Thomas RC, Aristoff PA, Tarpley WG et al (1994) Kinetic studies with the non-nucleoside human immunodeficiency virus type-1 reverse transcriptase inhibitor U-90152E. Biochem Pharmacol 47(11):2017–2028PubMedCrossRefGoogle Scholar
  70. 70.
    Souza TM, Rodrigues DQ, Ferreira VF, Marques IP, da Costa Santos F, Cunha AC, de Souza MC, de Palmer Paixao Frugulhetti IC, Bou-Habib DC, Fontes CF (2009) Characterization of HIV-1 enzyme reverse transcriptase inhibition by the compound 6-chloro-1,4-dihydro-4-oxo-1-(beta-D-ribofuranosyl) quinoline-3- carboxylic acid through kinetic and in silico studies. Curr HIV Res 7(3):327–335PubMedCrossRefGoogle Scholar
  71. 71.
    Pitta E, Geronikaki A, Surmava S, Eleftheriou P, Mehta V, Van der Eicken E (2013) Synthesis and HIV-1 RT inhibitory action of novel (4/6-substituted benzo[d]thiazol -2-yl)thiazolidin-4-ones. Divergence from the noncompetitive mechanism. J Enzyme Inhib Med Chem 28(1):113–122PubMedCrossRefGoogle Scholar
  72. 72.
    Andries K, Azijn H, Thielemans T, Ludovici D, Kukla M, Heeres J, Janssen P, De Corte B, Vingerhoets J, Pauwels R, de Bethune MP (2004) TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother 48(12):4680–4686PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Zhan P, Liu X, Li Z, Fang Z, Li Z, Wang D, Pannecouque C, De Clercq E (2008) Novel 1,2,3-thiadiazole derivatives as HIV-1 NNRTIs with improved potency: synthesis and preliminary SAR studies. Acta Pharm 57:379–393Google Scholar
  74. 74.
    Rao A, Balzarini J, Carbone A, Chimirri A, De Clercq E, Monforte AM, Monforte P, Pannecouque C, Zappala M (2004) 2-(2,6-Dihalophenyl)-3-(pyrimidin-2-yl)-1,3-thiazolidin-4-ones as non-nucleoside HIV-1 reverse transcriptase inhibitors. Antiviral Res 63:79–84PubMedCrossRefGoogle Scholar
  75. 75.
    Debyser Z, Pauwels R, Andries K, Desmyter J, Kukla M, Janssen PA, De Clercq E (1991) An antiviral target on reverse transcriptase of human immunodeficiency virus type 1 revealed by tetrahydroimidazo-[4,5,1-jk][1,4]benzodiazepin-2 (1H)-one and -thione derivatives. Proc Natl Acad Sci U S A 88(4):1451–1455PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Goldman ME, Nunberg JH, O’Brien JA, Quintero JC, Schleif WA, Freund KF, Gaul SL, Saari WS, Wai JS, Hoffman JM et al (1991) Pyridinone derivatives: specific human immunodeficiency virus type 1 reverse transcriptase inhibitors with antiviral activity. Proc Natl Acad Sci U S A 88(15):6863–6867PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Miyasaka T, Tanaka H, Baba M, Hayakawa H, Walker RT, Balzarini J, De Clercq E (1989) A novel lead for specific anti-HIV-1 agents: 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine. J Med Chem 32(12):2507–2509PubMedCrossRefGoogle Scholar
  78. 78.
    Baba M, Tanaka H, De Clercq E, Pauwels R, Balzarini J, Schols D, Nakashima H, Perno CF, Walker RT, Miyasaka T (1989) Highly specific inhibition of human immunodeficiency virus type 1 by a novel 6-substituted acyclouridine derivative. Biochem Biophys Res Commun 165(3):1375–1381PubMedCrossRefGoogle Scholar
  79. 79.
    Rawal RK, Tripathi R, Kulkarni S, Paranjape R, Katti SB, Pannecouque C, De Clercq E (2008) 2-(2,6-Dihalo-phenyl)-3-heteroaryl-2-ylmethyl-1, 3-thiazolidin-4-ones: anti-HIV agents. Chem Biol Drug Des 72(2):147–154PubMedCrossRefGoogle Scholar
  80. 80.
    Brzozowski Z, Saczewski F, Neamati N (2006) Synthesis, antitumor and anti-HIV activities of benzodithiazine-dioxides. Bioorg Med Chem 14:2985–2993PubMedCrossRefGoogle Scholar
  81. 81.
    Novikov MS, Valuev-Elliston VT, Babkov DA, Paramonova MP, Ivanov AV, Gavryushov SA, Khandazhinskaya AL, Kochetkov SN, Pannecouque C, Andrei G, Snoeck R, Balzarini J, Seley-Radtke KL (2013) N1, N3-disubstituted uracils as nonnucleoside inhibitors of HIV-1 reverse transcriptase. Bioorg Med Chem 21:1150–1158PubMedCrossRefGoogle Scholar
  82. 82.
    Wang Y-P, Chen F-E, De Clercq E, Balzarini J, Pannecouque C (2009) Synthesis and in vitro anti-HIV evaluation of a new series of 6-arylmethyl-substituted S-DABOs as potential non-nucleoside HIV-1 reverse transcriptase inhibitors. Eur J Med Chem 41:1016–1023CrossRefGoogle Scholar
  83. 83.
    La Regina G, Coluccia A, Piscitelli F, Bergamini A, Sinistro A, Cavazza A, Maga J, Samuele A, Zanoli S, Novellino E, Artico M, Silvestri R (2007) Indolyl aryl sulfones as HIV-1 non-nucleoside reverse transcriptase inhibitors: role of two halogen atoms at the indole ring in developing new analogues with improved antiviral activity. J Med Chem 50:5034–5038PubMedCrossRefGoogle Scholar
  84. 84.
    Balzarini J, Orzeszko B, Maurin JK, Orzeszko A (2007) Synthesis and anti-HIV studies of 2-adamantyl-substituted thiazolidin-4-ones. Eur J Med Chem 42:993–1003PubMedCrossRefGoogle Scholar
  85. 85.
    Akkouh O, Tzi Bun N, Singh SS, Yin C, Dan X, Chan YC, Pan W, Cheung RCF (2015) Lectins with anti-HIV activity: a review. Molecules 20:648–668PubMedCrossRefGoogle Scholar
  86. 86.
    Famiglini V, Coluccia A, Brancale A, Pelliccia S, La Regina G, Silvestri R (2013) Arylsulfone-based HIV-1 non-nucleoside reverse transcriptase inhibitors. Future Med Chem 5(18):2141–2156PubMedCrossRefGoogle Scholar
  87. 87.
    De Clercq E (2013) Dancing with chemical formulae of antivirals: a personal account. Biochem Pharmacol 86(6):711–725PubMedCrossRefGoogle Scholar
  88. 88.
    Veljkovic N, Glisic S, Prljic J, Perovic V, Veljkovic V (2013) Simple and general criterion for “in silico” screening of candidate HIV drugs. Curr Pharm Biotechnol 14(5):561–569PubMedCrossRefGoogle Scholar
  89. 89.
    Li D, Zhan P, Liu H, Pannecouque C, Balzarini J, De Clercq E, Liu X (2013) Synthesis and biological evaluation of pyridazine derivatives as novel HIV-1 NNRTIs. Bioorg Med Chem 21:2128–2134PubMedCrossRefGoogle Scholar
  90. 90.
    La Regina G, Coluccia A, Brancale A, Piscitelli F, Gatti V, Maga G, Samuele A, Pannecouque C, Schols D, Balzarini J, Novellino E, Silvestri R (2011) Indolylarylsulfones as HIV-1 non-nucleoside reverse transcriptase inhibitors: new cyclic substituents at indole-2-carboxamide. J Med Chem 54:1587–1598PubMedCrossRefGoogle Scholar
  91. 91.
    La Regina G, Coluccia A, Brancale A, Piscitelli F, Famiglini V, Cosconati S, Maga G, Samuele A, Gonzalez E, Clotet B, Schols D, Esté JA, Novellino E, Silvestri R (2012) New nitrogen containing substituents at the indole-2-carboxamide yield high potent and broad spectrum indolylarylsulfone HIV-1 non-nucleoside reverse transcriptase inhibitors. J Med Chem 55:6634–6638PubMedCrossRefGoogle Scholar
  92. 92.
    Rotili D, Samuele A, Tarantino D, Ragno R, Musmuca I, Ballante F, Botta G, Morera L, Pierini M, Cirilli R, Nawrozkij MB, Gonzalez E, Clotet B, Artico M, Esté JA, Maga G, Mai A (2012) 2-(Alkyl/aryl)amino-6-benzylpyrimidin-4(3H)-ones as inhibitors of wild-type and mutant HIV-1: enantioselectivity studies. J Med Chem 55:3558–3562PubMedCrossRefGoogle Scholar
  93. 93.
    Rawal RK, Tripathi R, Katti SB, Pannecouque C, De Clercq E (2008) Design and synthesis of 2-(2,6-dibromophenyl)-3-heteroaryl-1,3-thiazolidin-4-ones as anti-HIV agents. Eur J Med Chem 43:2800–2806PubMedCrossRefGoogle Scholar
  94. 94.
    Ravichandran S, Veerasamy R, Raman S, Krishnan PN, Agrawal RK (2008) An overview on HIV-1 reverse transcriptase inhibitors. Dig J Nanomater Biostruct 3(4):171–187Google Scholar
  95. 95.
    Paolucci S, Baldanti F, Tinelli M et al (2002) Q145M, a novel HIV-1 reverse transcriptase mutation conferring resistance to nucleoside and nonnucleoside reverse transcriptase inhibitors. Antivir Ther 7(2):S35Google Scholar
  96. 96.
    Johnson VA, Brun-Vezinet F, Clotet B, Conway B, D’Acquila RT, Demeter LM, Kuritzkes DR, Pillay D, Shapiro JM, Telenta A, Richman DD (2004) Update of the drug resistance mutations in HIV-1: 2004. Top HIV Med 12(4):119–124PubMedGoogle Scholar
  97. 97.
    Mbuagbaw LC, Irlam JH, Spaulding A, Rutherford GW, Siegfried N (2010) Efavirenz or nevirapine in three-drug combination therapy with two nucleoside-reverse transcriptase inhibitors for initial treatment of HIV infection in antiretroviral-naive individuals. Cochrane Database Syst Rev 8(12):CD004246Google Scholar
  98. 98.
    Neukam K, Mira JA, Ruiz-Morales J, Rivero A, Collado A, Torres-Cornejo A, Merino D, de Los Santos-Gil I, Macias J, Gonzalez-Serrano M, Camacho A, Parra-Garcia G, Pineda JA, On behalf of the SEGURIDAD HEPATICA Study Team of the Grupo HEPAVIR de la Sociedad Andaluza de Enfermedades Infecciosas (SAEI) (2011) Liver toxicity associated with antiretroviral therapy including efavirenz or ritonavir-boosted protease inhibitors in a cohort of HIV/hepatitis C virus co-infected patients. J Antimicrob Chemother 66(11):2605–2614PubMedCrossRefGoogle Scholar
  99. 99.
    Esposito F, Corona A, Tramontan E (2012) HIV-1 reverse transcriptase still remains a new drug target: structure, function, classical inhibitors, and new inhibitors with innovative mechanisms of actions. Mol Biol Int 2012:586401PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Jochmans D, Deval J, Kesteleyn B, Van Marck H, Bettens E, De Baere I, Dehertogh P, Ivens T, Van Ginderen M, Van Schoubroeck B, Ethesami M, Wigerinck P, Gotte M, Hertogs K, Hertogs K (2006) Indolopyridones inhibit human immunodeficiency virus reverse transcriptase with a novel mechanism of action. J Virol 80(24):12283–12292PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Zhang Z, Walker M, Xu W, Shim JH, Giradet J-L, Hamatake RK, Hong Z (2006) Novel nonnucleoside inhibitors that select nucleoside inhibitor resistance mutations in human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother 50(8):2772–2781PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Maga G, Radi M, Zanoli S, Manetti F, Cancio R, Hübscher U, Spadari S, Falciani C, Terrazas M, Vilarrasa J, Botta M (2007) Discovery of non-nucleoside inhibitors of HIV-1 reverse transcriptase competing with the nucleotide substrate. Angew Chem 16(11):1810–1813CrossRefGoogle Scholar
  103. 103.
    Radi M, Falciani C, Contemori L, Petricci E, Maga G, Samuele A, Zanoli S, Terrazas M, Castria M, Togninelli A, Este JA, Clotet-Codina I, Armand-Ugon M, Botta M (2008) A multidisciplinary approach for the identification of novel HIV-1 non-nucleoside reverse transcriptase inhibitors: S-DABOCs and DAVPs. ChemMedChem 3(4):573–593PubMedCrossRefGoogle Scholar
  104. 104.
    Freisz S, Bec G, Radi M, Wolff P, Crespan E, Angeli L, Dumas P, Maga G, Botta M, Ennifar E (2010) Crystal structure of HIV-1 reverse transcriptase bound to a non-nucleoside inhibitor with a novel mechanism of action. Angew Chem Int Ed Engl 49:1805–1808PubMedCrossRefGoogle Scholar
  105. 105.
    Wang JY, Ling H, Yang W, Craigie R (2001) Structure of a two-domain fragment of hiv-1 integrase: implications for domain organization in the intact protein. EMBO J 20:7333–7343PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Lodi PJ, Ernst JA, Kuszewski J, Hickman AB, Engelman A, Craigie R, Clore GM, Gronenborn AM (1995) Solution structure of the DNA binding domain of HIV-1 integrase. Biochemistry 34(31):9826–9833PubMedCrossRefGoogle Scholar
  107. 107.
    Rhodes DI, Peat TS, Vandegraaff N, Jeevarajah D, Newman J, Martyn J, Coates JA, Ede NJ, Rea P, Deadman JJ (2011) Crystal structures of novel allosteric peptide inhibitors of HIV integrase identify new interactions at the LEDGF binding site. Chembiochem 12(15):2311–2315PubMedCrossRefGoogle Scholar
  108. 108.
    Sharma A, Slaughter A, Jena N, Feng L, Kessl JJ, Fadel HJ, Malani N, Male F, Wu L, Poeschla E, Bushman FD, Fuchs JR, Kvaratskhelia M (2014) A new class of multimerization selective inhibitors of HIV-1 integrase. Plos Pathog 10(5):e1004171PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Wielens J, Headey SJ, Rhodes DI, Mulder RJ, Dolezal O, Deadman JJ, Newman J, Chalmers DK, Parker MW, Peat TS, Scanlon MJ (2013) Parallel screening of low molecular weight fragment libraries: do differences in methodology affect hit identification? J Biomol Screen 18:147–159PubMedCrossRefGoogle Scholar
  110. 110.
    Hazuda DJ, Felock P, Witmer M, Wolfe A, Stillmock K, Grobler JA, Espeseth A, Gabryelski L, Schleif W, Blau C, Miller MD (2000) Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 287(5453):646–650PubMedCrossRefGoogle Scholar
  111. 111.
    Pommier Y, Johnson AA, Marchand C (2005) Integrase inhibitors to treat HIV/AIDS. Nat Rev Drug Discov 4(3):236–248PubMedCrossRefGoogle Scholar
  112. 112.
    Wai JS, Egbertson MS, Payne LS, Fisher TE, Embrey MW, Tran LO, Melamed JY, Langford HM, Guare JP Jr, Zhuang L, Grey VE, Vacca JP, Holloway MK, Naylor-Olsen AM, Hazuda DJ, Felock PJ, Wolfe AL, Stillmock KA, Schleif WA, Gabryelski LJ, Young SD (2000) 4-Aryl-2,4-dioxobutanoic acid inhibitors of HIV-1 integrase and viral replication in cells. J Med Chem 43(26):4923–4926PubMedCrossRefGoogle Scholar
  113. 113.
    Grobler JA, Stillmock K, Hu B, Witmer M, Felock P, Espeseth AS, Wolfe A, Egbertson M, Bourgeois M, Melamed J, Way JS, Young S, Vacca J, Hazuda DJ (2002) Diketo acid inhibitor mechanism and HIV-1 integrase: implications for metal binding in the active site of phosphotransferase enzymes. Proc Natl Acad Sci 99(10):6661–6666PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Marchand C, Johnson AA, Karki RG, Pais GC, Zhang X, Cowansage K, Patel TA, Nicklaus M, Burke TR Jr, Pommier Y (2003) Metal-dependent inhibition of HIV-1 integrase by beta-diketo acids and resistance of the soluble double-mutant (F185K/C280S). Mol Pharmacol 64(3):600–609PubMedCrossRefGoogle Scholar
  115. 115.
    Hazuda DJ, Young SD, Guare JP, Anthony NJ, Gomez RP, Wai JS, Vacca JP, Handt L, Motzel SL, Klein HJ, Dornadula G, Danovich RM, Witmer MV, Wilson KA, Tussey L, Schleif WA, Gabryelski LS, Jin L, Miller MD, Casimiro DR, Emini EA, Shiver JW (2004) Integrase inhibitors and cellular immunity suppress retroviral replication in rhesus macaques. Science 305(5683):528–532PubMedCrossRefGoogle Scholar
  116. 116.
    Asante-Appiah E, Skalka AM (1999) HIV-1 integrase: structural organization, conformational changes, and catalysis. Adv Virus Res 52:351–369PubMedCrossRefGoogle Scholar
  117. 117.
    Esposito D, Craigie R (1999) HIV integrase structure and function. Adv Virus Res 52:319–333PubMedCrossRefGoogle Scholar
  118. 118.
    Summa V, Petrocchi A, Matassa VG, Gardelli C, Muraglia E, Rowley M, Paz OG, Laufer R, Monteagudo E, Pace P (2006) 4,5-Dihydroxypyrimidine carboxamides and N-alkyl-5-hydroxypyrimidinone carboxamides are potent, selective HIV integrase inhibitors with good pharmacokinetic profiles in preclinical species. J Med Chem 49(23):6646–6649PubMedCrossRefGoogle Scholar
  119. 119.
    Savarino A (2006) A historical sketch of the discovery and development of HIV-1 integrase inhibitors. Expert Opin Investig Drugs 15(12):1507–1522PubMedCrossRefGoogle Scholar
  120. 120.
    Iwamoto M, Wenning LA, Petry AS, Laethem M, De Smet M, Kost JT, Merschman SA, Strohmaier KM, Ramael S, Lasseter KC, Stone JA, Gottesdiener KM, Wagner JA (2008) Safety, tolerability, and pharmacokinetics of raltegravir after single and multiple doses in healthy subjects. Clin Pharmacol Ther 83(2):293–299PubMedCrossRefGoogle Scholar
  121. 121.
    DeJesus E, Berger D, Markowitz M, Cohen C, Hawkins T, Ruane P, Elion R, Farthing C, Zhong L, Cheng AK, McColl D, Kearney BP (2006) Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients. J Acquir Immune Defic Syndr 43(1):1–5PubMedCrossRefGoogle Scholar
  122. 122.
    Temesgen Z, Siraj DS (2008) Raltegravir: first in class HIV integrase inhibitor. Ther Clin Risk Manag 4(2):493–500PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Mouscadet J-F, Tchertanov L (2009) Raltegravir: molecular basis of its mechanism of action. Eur J Med Res 14(Suppl III):5–16PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Shimura KL, Kodama EN (2009) Elvitegravir: a new HIV integrase inhibitor. Antivir Chem Chemother 20(2):79–85PubMedCrossRefGoogle Scholar
  125. 125.
    Fantauzzi A, Turriziani O, Mezzaroma I (2013) Potential benefit of dolutegravir once daily: efficacy and safety. HIV AIDS (Auckl) 5:29–40Google Scholar
  126. 126.
    Malet I, Delelis O, Valantin M-A, Montes B, Soulie C, Wirden M, Tchertanov L, Peytavin G, Reynes J, Mouscadet J-F, Katlama C, Calvez V, Marcelin A-G (2008) Mutations associated with failure of raltegravir treatment affect integrase sensitivity to the inhibitor in vitro. Antimicrob Agents Chemother 52(4):1351–1358PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Métifiot M, Marchand C, Maddali K, Pommier Y (2010) Resistance to integrase inhibitors. Viruses 2(7):1347–1366PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Kobayashi M, Yoshinaga T, Seki T, Wakasa-Morimoto C, Brown KW, Ferris R, Foster SA, Hazen RJ, Miki S, Suyama-Kagitani A, Kawauchi-Miki S, Taishi T, Kawasuji T, Johns BA, Underwood MR, Garvey EP, Sato A, Fujiwara T (2011) In Vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor. Antimicrob Agents Chemother 55(2):813–821PubMedCrossRefGoogle Scholar
  129. 129.
    Pommier Y, Marchand C, Neamati N (2000) Retroviral inhibition of HIV-1 vector integrase inhibitors year 2000: update and perspectives. Antiviral Res 47:139–148PubMedCrossRefGoogle Scholar
  130. 130.
    Neamati N, Marchand C, Pommier Y (2000) HIV-1 integrase inhibitors: past, present, and future. Adv Pharmacol 49:147–165PubMedCrossRefGoogle Scholar
  131. 131.
    Young SD (2001) Inhibition of HIV-1 integrase by small molecules: the potential for a new class of AIDS chemotherapeutics. Curr Opin Drug Discov Devel 4:402–410PubMedGoogle Scholar
  132. 132.
    Pannecouque C, Pluymers W, Van Maele B, Tetz V, Cherepanov P, De Clercq E, Debyser Z (2002) New class of HIV integrase inhibitors that block viral replication in cell culture. Curr Biol 12:1169–1177PubMedCrossRefGoogle Scholar
  133. 133.
    Brzozowski Z, Saczewski F, Sławiński J, Sanchez T, Neamati N (2009) Synthesis and anti-HIV-1 integrase activities of 3-aroyl-2,3-dihydro-1,1-dioxo-1,4,2-benzodithiazines. Eur J Med Chem 44:190–196PubMedCrossRefGoogle Scholar
  134. 134.
    Johnson TW, Tanis SP, Butler SL, Dalvie D, DeLisle DM, Dress KR, Flahive EJ, Hu Q, Kuehler JE, Kuki A, Liu W, McClellan GA, Peng Q, Plewe MB, Richardson PF, Smith GL, Solowiej J, Tran KT, Yu HWX, Zhang J, Zhu H (2011) Design and synthesis of novel N-hydroxy-dihydronaphthyridinones as potent and orally bioavailable HIV-1 integrase inhibitors. J Med Chem 54:3393–3417PubMedCrossRefGoogle Scholar
  135. 135.
    Kawasuji T, Johns BA, Yoshida H, Taishi T, Taoda Y, Murai H, Kiyama R, Fuji M, Yoshinaga T, Seki T, Kobayashi M, Sato A, Fujiwara T (2012) Carbamoyl pyridone HIV-1 integrase inhibitors. 1. Molecular design and establishment of an advanced two-metal binding pharmacophore. J Med Chem 55(20):8735–8744PubMedCrossRefGoogle Scholar
  136. 136.
    Tsiang M, Jones GS, Niedziela-Majka A, Kan E, Lansdon EB, Huang W, Hung M, Samuel D, Novikov N, Xu Y, Mitchell M, Guo H, Babaoglu K, Liu X, Geleziunas R, Sakowicz R (2012) New class of HIV-1 integrase (in) inhibitors with a dual mode of action. J Biol Chem 287:21189–21203PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Seelmeier S, Schmidt H, Turk V, von der Helm K (1988) Human immunodeficiency virus has an aspartic-type protease that can be inhibited by pepstatin A. Proc Natl Acad Sci U S A 85:6612–6616PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Kohl NE, Emini EA, Schleif WA, Davis LJ, Heimbach JC, Dixon RA, Scolnik EM, Sigal IS (1988) Active human immunodeficiency virus protease is required for viral infectivity. Proc Natl Acad Sci U S A 85:4686–4690PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Degoey DA, Grampovnik DJ, Flentge CA, Flosi WJ, Chen HJ, Yeung CM, Randolph JT, Klein LL, Dekhtyar T, Colletti L, Marsh KC, Stoll V, Mamo M, Morfitt DC, Nguyen B, Schmidt JM, Swanson SJ, Mo H, Kati WM, Molla A, Kempf DJ (2009) 2-pyridyl p1′-substituted symmetry-based human immunodeficiency virus protease inhibitors (A-792611 and a-790742) with potential for convenient dosing and reduced side effects. J Med Chem 52:2571–2586PubMedCrossRefGoogle Scholar
  140. 140.
    McQuade TJ, Tomasselli AG, Liu L, Karacostas B, Moss B, Sawyer TK, Heinrikson RL, Tarpley WG (1990) A synthetic HIV protease inhibitor with antiviral activity arrests HIV-like particle maturation. Science 247:454–4566PubMedCrossRefGoogle Scholar
  141. 141.
    Tang J, Lin Y, Co E, Hartsuck J, Lin X (1992) Understanding protease: can it be translated into effective therapy against AIDS. Scand J Clin Lab Invest 52(Suppl 210):127–135CrossRefGoogle Scholar
  142. 142.
    Brik A, Wong CH (2003) HIV-1 protease: mechanism and drug discovery. Org Biomol Chem 1(1):5–14PubMedCrossRefGoogle Scholar
  143. 143.
    Kurup A, Mekapati SB, Garg R, Hansch C (2003) HIV-1 protease inhibitors: a comparative QSAR analysis. Curr Med Chem 10:1679–1688PubMedCrossRefGoogle Scholar
  144. 144.
    Perez MAS, Fernandes PA, Ramos MJ (2007) Drug design: new inhibitors for HIV-1 protease based on Nelfinavir as lead. J Mol Graph Model 26:634–642PubMedCrossRefGoogle Scholar
  145. 145.
    Larder BA et al (2000) Tipranavir inhibits broadly protease inhibitor-resistant HIV-1 clinical samples. AIDS 14:1943–1948PubMedCrossRefGoogle Scholar
  146. 146.
    Zeldin RK, Petruschke RA (2004) Pharmacological and therapeutic properties of ritonavir-boosted protease inhibitor therapy in HIV-infected patients. J Antimicrob Chemother 53(1):4–9PubMedCrossRefGoogle Scholar
  147. 147.
    Flentge CA, Randolph JT, Huang PP, Klein LL, Marsh KC, Harlan JE, Kempf DJ (2009) Synthesis and evaluation of inhibitors of cytochrome P450 3A (CYP3A) for pharmacokinetic enhancement of drugs. Bioorg Med Chem Lett 19:5444–5448PubMedCrossRefGoogle Scholar
  148. 148.
    Sperka T, Pitlik J, Bagossia P, Tozser J (2005) Beta-lactam compounds as apparently uncompetitive inhibitors of HIV-1 protease. Bioorg Med Chem Lett 15:3086–3090PubMedCrossRefGoogle Scholar
  149. 149.
    Bisacchi GS, Slusarchyk VA, Bolton SA, Hartl KS, Jacobs G, Mathur A, Meng W, Ogletree ML, Pi Z, Sutton JC, Treuner U, Zahle R, Zhao G, Seiler SM (2004) Synthesis of potent and highly selective nonguanidine azetidinone inhibitors of human tryptase. Bioorg Med Chem Lett 14:2227–2231PubMedCrossRefGoogle Scholar
  150. 150.
    Sutton JC, Bolton SA, Davis ME, Hartl KS, Jacobson B, Mathur A, Ogletree ML, Slusarchyk WA, Zahler SSM, Bisacchi GS (2004) Solid-phase synthesis and SAR of 4-carboxy-2-azetidinone mechanism-based tryptase inhibitors. Bioorg Med Chem Lett 14:2233–2239PubMedCrossRefGoogle Scholar
  151. 151.
    Stebbins J, Beboucl C (1997) A microtiter colorimetric assay for the HIV-1 protease. Anal Biochem 248(2):246–250PubMedCrossRefGoogle Scholar
  152. 152.
    Pitlik J, Townsend CA (1997) Solution-phase synthesis of a combinatorial monocyclic β-lactam library: potential protease inhibitors. Bioorg Med Chem Lett 7:3129–3133CrossRefGoogle Scholar
  153. 153.
    Tözsér J, Gustchina A, Weber IT, Blaha I, Wondrak EM, Oroszlan S (1991) Studies on the role of the S4 substrate binding site of HIV proteinases. FEBS Lett 279(2):356–360PubMedCrossRefGoogle Scholar
  154. 154.
    Wondrak EM, Louis JM, Oroszlan S (1991) purification of HIV-1 wild-type protease and characterization of proteolytically inactive HIV-1 protease mutants by pepstatin A affinity chromatography. FEBS Lett 280:347–350PubMedCrossRefGoogle Scholar
  155. 155.
    Bagossi P, János Kádas J, Gabriella Miklóssy G, Boross P, Weber IT, Tözsér J (2004) Development of a microtiter plate fluorescent assay for inhibition studies on the HTLV-1 and HIV-1 proteinases. J Virol Methods 119:87–93PubMedCrossRefGoogle Scholar
  156. 156.
    Cígler P, Kožíšek M, Řezáčová P, Brynda J, Otwinowski Z, Pokorná J, Plešek J, Grüner B, Dolečková-Marešová L, Máša M, Sedláček J, Bodem J, Kräusslich H-G, Král V, Konvalinka J (2005) From nonpeptide toward noncarbon protease inhibitors: metallacarboranes as specific and potent inhibitors of HIV protease. Proc Natl Acad Sci U S A 102(43):15394–15399PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Ghosh AK, Anderson DD (2011) Tetrahydrofuran, tetrahydropyran, triazoles and related heterocyclic derivatives as HIV protease inhibitors. Future Med Chem 3(9):1181–1197PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Wang RR, Gao Y-D, Ma C-H, Zhang X-J, Huang C-G, Huang J-F, Zheng Y-T (2011) Mangiferin, an anti-HIV-1 agent targeting protease and effective against resistant strains. Molecules 16:4264–4277PubMedCrossRefGoogle Scholar
  159. 159.
    Jonckers THM, Rouan M-C, Hachι G, Schepens W, Hallenberger S, Baumeister J, Sasaki JC (2012) Benzoxazole and benzothiazole amides as novel pharmacokinetic enhancers of HIV protease inhibitors. Bioorg Med Chem Lett 22:4998–5002PubMedCrossRefGoogle Scholar
  160. 160.
    Surleraux DLNG, Tahri A, Verschueren WG, Pille GME, de Kock HA, Jonckers THM, Peeters A, De Meyer S, Azijn H, Pauwels R, de Bethune M-P, King NM, Prabu-Jeyabalan M, Schiffer CA, Wigerinck PBTP (2005) Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor. J Med Chem 48:1813–1822PubMedCrossRefGoogle Scholar
  161. 161.
    Manchanda T, Schiedel D, Fischer D, Dekaban GA, Rieder MJ (2002) Adverse drug reactions to protease inhibitors. Can J Clin Pharmacol 9(3):137–146, FallPubMedGoogle Scholar
  162. 162.
    Hui DY (2003) Effects of HIV protease inhibitor therapy on lipid metabolism. Prog Lipid Res 42(2):81–92PubMedCrossRefGoogle Scholar
  163. 163.
    Friis-Moller N, Weber R, Reiss P, Thiιbaut R, Kirk O, Monforte AD, Pradier C, Morfeldt L, Mateu S, Law M, El-Sadr W, DeWit S, Sabin CA, Phillips AN, Lundgren JD (2003) Cardiovascular disease risk factors in HIV patients—association with antiretroviral therapy: results from the DAD study. AIDS 17:1179–1193PubMedCrossRefGoogle Scholar
  164. 164.
    Friis-Moller N, Reiss P, Sabin CA, Weber R, Monforte AD, El-Sadr W, Thiιbaut R, DeWit S, Kirk O, Fontas E, Law MG, Phillips A, Lundgren JD (2007) Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med 356:1723–1735PubMedCrossRefGoogle Scholar
  165. 165.
    Smith C, Sabin CA, Lundgren JD, Thiebaut R, Weber R, Law RM, Monforte AD, Kirk O, Friis-Moller N, Phillips A, Reiss P, El Sadr W, Pradier C, Worm SW (2010) Factors associated with specific causes of death amongst HIV-positive individuals in the DAD study. AIDS 24:1537–1548PubMedCrossRefGoogle Scholar
  166. 166.
    Zaera M, Miro O, Pedrol E, Soler A, Picon M, Cardellach F, Casademont J, Nunes V (2001) Mitochondrial involvement in antiretroviral therapy-related lipodystrophy. AIDS 15:1643–1651PubMedCrossRefGoogle Scholar
  167. 167.
    Zhang S, Carper MJ, Lei X, Cade WT, Yarashesk KE, Ramanadham S (2009) Protease inhibitors used in the treatment of HIV+ induce beta-cell apoptosis via the mitochondrial pathway and compromise insulin secretion. Am J Physiol Endocrinol Metab 296:E925–E935PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Lagathu C, Eustace B, Prot M, Frantz D, Gu Y, Bastard J-P, Maachi M, Azoulay S, Briggs M, Caron M, Capeau J (2007) Some HIV antiretrovirals increase oxidative stress and alter chemokine, cytokine or adiponectin production in human adipocytes and macrophages. Antivir Ther 12:489–500PubMedGoogle Scholar
  169. 169.
    Chandra S, Mondal D, Agrawal KS (2009) HIV-1 protease inhibitor induced oxidative stress suppresses glucose stimulated insulin release: protection with thymoquinone. Exp Biol Med 234:442–453CrossRefGoogle Scholar
  170. 170.
    Touzet O, Philips A (2010) Resveratrol protects against protease inhibitor-induced reactive oxygen species production, reticulum stress and lipid raft perturbation. AIDS 24:1437–1447PubMedCrossRefGoogle Scholar
  171. 171.
    Ben-Romano R, Rudich A, Etzion S, Potashnik R, Kagan E, Greenbaum U, Bashan N (2006) Nelfinavir induces adipocyte insulin resistance through the induction of oxidative stress: differential protective effect of antioxidant agents. Antivir Ther 11:1051–1060PubMedGoogle Scholar
  172. 172.
    Wang X, Chai H, Lin PH, Yao Q, Chen C (2009) Roles and mechanisms of human immunodeficiency virus protease inhibitor ritonavir and other anti-human immunodeficiency virus drugs in endothelial dysfunction of porcine pulmonary arteries and human pulmonary artery endothelial cells. Am J Pathol 174:771–781PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Wang X, Mu H, Chai H, Liao D, Yao Q, Chen C (2007) Human immunodeficiency virus protease inhibitor ritonavir inhibits cholesterol efflux from human macrophage-derived foam cells. Am J Pathol 171:304–314PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Conklin BS, Fu W, Lin PH, Lumsden AB, Yao Q, Chen C (2004) HIV protease inhibitor ritonavir decreases endothelium-dependent vasorelaxation and increases superoxide in porcine arteries. Cardiovasc Res 63:168–175PubMedCrossRefGoogle Scholar
  175. 175.
    Chai H, Yang H, Yan S, Li M, Lin PH, Lumsden AB, Yao Q, Chen C (2005) Effects of HIV protease inhibitors on vasomotor function and superoxide anion production in porcine coronary arteries. J Acquir Immune Defic Syndr 40:12–19PubMedCrossRefGoogle Scholar
  176. 176.
    Kilby JM, Hopkins S, Venetta TM, DiMassimo B, Cloud GA, Lee JY, Alldredge L, Hunter E, Lambert D, Bolognesi D, Matthews T, Johnson MR, Nowak MA, Shaw GM, Saag MS (1998) Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat Med 4(11):1302–1307PubMedCrossRefGoogle Scholar
  177. 177.
    Robertson D (2003) US FDA approves new class of HIV therapeutics. Nat Biotechnol 21(5):470–471PubMedCrossRefGoogle Scholar
  178. 178.
    Este JA, Telenti A (2007) HIV entry inhibitors. Lancet 370(9581):81–88PubMedCrossRefGoogle Scholar
  179. 179.
    Tan Q, Zhu Y, Li J, Chen Z, Han GW, Kufareva I, Li T, Ma L, Fenalti G, Li J, Zhang W, Xie X, Yang H, Jiang H, Cherezov V, Liu H, Stevens RC, Zhao Q, Wu B (2013) Structure of the CCR5 chemokine receptor-HIV entry inhibitor maraviroc complex. Science 341:1387–1390PubMedCrossRefGoogle Scholar
  180. 180.
    Marcial M, Lu J, Deeks SG, Ziermann R, Kuritzkes DR (2006) Performance of human immunodeficiency virus type 1 gp41 assays for detecting enfuvirtide (T-20) resistance mutations. J Clin Microbiol 44(9):3384–3387PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    Rimsky LT, Shugars DC, Matthews TJ (1998) Determinants of human immunodeficiency virus type 1 resistance to gp41-derived inhibitory peptides. J Virol 72:986–993PubMedPubMedCentralGoogle Scholar
  182. 182.
    Sista PR, Melby T, Davison D, Jin L, Mosier S, Mink M, Nelson EL, DeMasi R, Cammack N, Salgo MP, Matthews TJ, Greenberg ML (2004) Characterization of determinants of genotypic and phenotypic resistance to enfuvirtide in baseline and on-treatment HIV-1 isolates. AIDS 18:1787–1794PubMedCrossRefGoogle Scholar
  183. 183.
    Marcelin AG, Reynes J, Yerly S, Ktorza N, Segondy M, Piot JC, Delfraissy JF, Kaiser L, Perrin L, Katlama C, Calvez V (2004) Characterization of genotypic determinants in HR-1 and HR-2 gp41 domains in individuals with persistent HIV viraemia under T-20. AIDS 18:1340–1342PubMedCrossRefGoogle Scholar
  184. 184.
    Mink M, Mosier SM, Janumpalli S, Davison D, Jin L, Melby T, Sista P, Erickson J, Lambert D, Stanfield-Oakley SA, Salgo M, Cammack N, Matthews T, Greenberg ML (2005) Impact of human immunodeficiency virus type 1 gp41 amino acid substitutions selected during enfuvirtide treatment on gp41 binding and antiviral potency of enfuvirtide in vitro. J Virol 79:12447–12454PubMedPubMedCentralCrossRefGoogle Scholar
  185. 185.
    Xu L, Pozniak A, Wildfire A, Stanfield-Oakley SA, Mosier SM, Ratcliffe D, Workman J, Joall A, Myers R, Smit E, Cane PA, Greenberg ML, Pillay D (2005) Emergence and evolution of enfuvirtide resistance following long-term therapy involves heptad repeat 2 mutations within gp41. Antimicrob Agents Chemother 49:1113–1119PubMedPubMedCentralCrossRefGoogle Scholar
  186. 186.
    Yao X, Chong H, Zhang C, Waltersperger S, Wang M, Cui S, He Y (2012) Broad antiviral activity and crystal structure of HIV-1 fusion inhibitor sifuvirtide. J Biol Chem 287:6788–6796PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    Jiang S, Tala SR, Lu H, Abo-Dya NE, Avan I, Gyanda K, Lu L, Katritzky AR, Debnath AK (2011) Design, synthesis, and biological activity of novel 5-((arylfuran/1H-pyrrol-2-yl)methylene)-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-4-ones as HIV-1 fusion inhibitors targeting gp41. J Med Chem 54:572–579PubMedCrossRefGoogle Scholar
  188. 188.
    Jiang S, Lu H, Liu S, Zhao Q, He Y, Debnath AK (2004) N-substituted pyrrole derivatives as novel human immunodeficiency virus type 1 entry inhibitors that interfere with the gp41 six helix bundle formation and block virus fusion. Antimicrob Agents Chemother 48:4349–4359PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    Katritzky AR, Tala SR, Lu H, Vakulenko AV, Chen Q-Y, Sivapackiam J, Pandya K, Jiang S, Debnath AK (2009) Design, synthesis, and structure-activity relationship of a novel series of 2-aryl 5-(4-oxo-3-phenethyl-2-thioxothiazolidinylidenemethyl) furans as HIV-1 entry inhibitors. J Med Chem 52:7631–7639PubMedPubMedCentralCrossRefGoogle Scholar
  190. 190.
    Teixeira C, Gomes JRB, Gomes P, Maurel F (2011) Viral surface glycoproteins, gp120 and gp41, as potential drug targets against HIV-1: brief overview one quarter of a century past the approval of zidovudine, the first anti-retroviral drug. Eur J Med Chem 46(4):979–992PubMedCrossRefGoogle Scholar
  191. 191.
    Acharya P, Lusvarghi S, Bewley CA, Kwong PD (2015) HIV-1 gp120 as a therapeutic target: navigating a moving labyrinth. Expert Opin Ther Targets 19(6):765–783PubMedPubMedCentralCrossRefGoogle Scholar
  192. 192.
    Dezube BJ, Dahl TA, Wong TK, Chapman B, Ono M, Yamaguchi N, Gillies SD, Chen LB, Crumpacker CS (2000) A fusion inhibitor (FP-21399) for the treatment of human immunodeficiency virus infection: a phase I study. J Infect Dis 182:607–610PubMedCrossRefGoogle Scholar
  193. 193.
    Hermann H, Westhof E (1998) RNA as a drug target: chemical, modeling, and evolutionary tools. Curr Opin Biotechnol 9:66–73PubMedCrossRefGoogle Scholar
  194. 194.
    Yang M (2005) Discoveries of Tat-Tar interaction inhibitors for HIV-1. Curr Drug Targets Infect Disord 5(4):433–444PubMedCrossRefGoogle Scholar
  195. 195.
    Gait MJ, Karn J (1993) RNA recognition by the human immunodeficiency virus Tat and Rev proteins. Trends Biochem Sci 18:255–259PubMedCrossRefGoogle Scholar
  196. 196.
    AbouI-Ela F, Karn J, Varani G (1995) The structure of the human immunodeficiency virus type-1 TAR RNA reveals principles of RNA recognition by Tat protein. J Mol Biol 253:313–332CrossRefGoogle Scholar
  197. 197.
    O’Brien WA, Sumner-Smith M, Mao SH, Sadeghi S, Zhao JQ, Chen IS (1996) Anti-human immunodeficiency virus type 1 activity of an oligocationic compound mediated via gp120 V3 interactions. J Virol 70:2825–2831PubMedPubMedCentralGoogle Scholar
  198. 198.
    Hamasaki K, Ueno A (2001) Aminoglycoside antibiotics, neamine and its derivatives as potent inhibitors for the RNA-protein interactions derived from HIV-1 activators. Bioorg Med Chem Lett 11:591–594PubMedCrossRefGoogle Scholar
  199. 199.
    Marciniak RA, Sharp PA (1991) HIV-1 Tat protein promotes formation of more-processive elongation complexes. EMBO J 10:4189–4196PubMedPubMedCentralCrossRefGoogle Scholar
  200. 200.
    Daelemans D, Este JA, Witvrouw M et al (1997) S-adenosylhomocysteine hydrolase inhibitors interfere with the replication of human immunodeficiency virus type 1 through inhibition of the LTR transactivation. Mol Pharmacol 52:1157–1163PubMedCrossRefGoogle Scholar
  201. 201.
    De Clercq E (1998) Carbocyclic adenosine analogues as S-adenosylhomocysteine hydrolase inhibitors and antiviral agents: recent advances. Nucleosides Nucleotides 17:625–634PubMedCrossRefGoogle Scholar
  202. 202.
    Ratmeyer L, Zapp ML, Green MR, Vinayak R, Kumar A, Boykin DW, Wilson WD (1996) Inhibition of HIM-1 Rev-RRE interaction by diphenylfuran derivatives. Biochemistry 35:13689–13696PubMedCrossRefGoogle Scholar
  203. 203.
    Kaufmann GR, Cooper DA (2000) Antiretroviral therapy of HIV-1 infection: established treatment strategies and new therapeutic options. Curr Opin Microbiol 3(5):508–514PubMedCrossRefGoogle Scholar
  204. 204.
    Richman DD (2001) HIV chemotherapy. Nature 410(6831):995–1001PubMedCrossRefGoogle Scholar
  205. 205.
    Lipshultz SE, Miller TL, Wilkinson JD, Scott GB, Somarriba G, Cochran TR, Fisher SD (2013) Cardiac effects in perinatally HIV-infected and HIV-exposed but uninfected children and adolescents: a view from the United States of America. J Int AIDS Soc 16(1):18597PubMedPubMedCentralCrossRefGoogle Scholar
  206. 206.
    Maldarelli F, Palmer S, King MS, Wiegand A, Polis MA, Mican J, Kovacs JA, Davey RT, Rock-Kress D, Dewar R, Liu S, Metcalf JA, Rehm C, Brun SC, Hanna GJ, Kempf DJ, Coffin JM, Mellors JW (2007) ART suppresses plasma HIV-1 RNA to a stable set point predicted by pretherapy viremia. PLoS Pathog 3(4):e46PubMedPubMedCentralCrossRefGoogle Scholar
  207. 207.
    Maartens G, Celum C, Lewin SR (2014) HIV infection: epidemiology, pathogenesis, treatment, and prevention. Lancet 384(9939):258–271PubMedCrossRefGoogle Scholar
  208. 208.
    Didigu C, Doms R (2014) Gene therapy targeting HIV entry. Viruses 6(3):1395–1409PubMedPubMedCentralCrossRefGoogle Scholar
  209. 209.
    Archin NM, Sung JM, Garrido C, Soriano-Sarabia N, Margolis DM (2014) Eradicating HIV-1 infection: seeking to clear a persistent pathogen. Nat Rev Microbiol 12(11):750–764PubMedPubMedCentralCrossRefGoogle Scholar
  210. 210.
    Siliciano JD, Siliciano RF (2014) Recent developments in the search for a cure for HIV-1 infection: targeting the latent reservoir for HIV-1. J Allergy Clin Immunol 134(1):12–19PubMedCrossRefGoogle Scholar
  211. 211.
    Manson McManamy ME, Hakre S, Verdin EM, Margolis DM (2014) Therapy for latent HIV-1 infection: the role of histone deacetylase inhibitors. Antivir Chem Chemother 23(4):145–149PubMedCrossRefGoogle Scholar
  212. 212.
    Bullen CK, Laird GM, Durand CM, Siliciano JD, Siliciano RF (2014) New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo. Nat Med 20(4):425–429PubMedPubMedCentralCrossRefGoogle Scholar
  213. 213.
    Archin NM, Bateson R, Tripathy MK, Crooks AM, Yang KH, Dahl NP, Kearney MF, Anderson EM, Coffin JM, Strain MC, Richman DD, Robertson KR, Kashuba AD, Bosch RJ, Hazuda DJ, Kuruc JD, Eron JJ, Margolis D (2014) HIV-1 expression within resting CD4+ T cells after multiple doses of vorinostat. J Infect Dis 210(5):728–735PubMedPubMedCentralCrossRefGoogle Scholar
  214. 214.
    Sogaard OS, Graversen ME, Leth S et al (2014) The HDAC inhibitor romidepsin is safe and effectively reverses HIV-1 latency in vivo as measured by standard clinical assays. In: 20th international AIDS conference, Melbourne, Abst TUAA0106LB, 20–25 July 2014Google Scholar
  215. 215.
    Newman DJ, Cragg GM (2012) Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod 75(3):311–335PubMedPubMedCentralCrossRefGoogle Scholar
  216. 216.
    Kumari A, Baskaran P, Van Staden J (2015) Enhanced HIV-1 reverse transcriptase inhibitory and antibacterial properties in callus of Catha edulis Forsk. Phytother Res 29(6):840–843PubMedCrossRefGoogle Scholar
  217. 217.
    Xu L, Grandi N, Del Vecchio C, Mandas D, Corona A, Piano D, Esposito F, Parolin C, Tramontano E (2015) From the traditional Chinese medicine plant Schisandra chinensis new scaffolds effective on HIV-1 reverse transcriptase resistant to non-nucleoside inhibitors. J Microbiol 53(4):288–293PubMedCrossRefGoogle Scholar
  218. 218.
    Huang SZ, Zhang X, Ma QY, Peng H, Zheng YT, Hu JM, Dai HF, Zhou J, Zhao YX (2014) Anti-HIV-1 tigliane diterpenoids from Excoecaria acertiflia Didr. Fitoterapia 95:34–41PubMedCrossRefGoogle Scholar
  219. 219.
    Ellithey MS, Lall N, Hussein AA, Meyer D (2014) Cytotoxic and HIV-1 enzyme inhibitory activities of Red Sea marine organisms. BMC Complement Altern Med 14:77PubMedPubMedCentralCrossRefGoogle Scholar
  220. 220.
    Helfer M, Koppensteiner H, Schneider M, Rebensburg S, Forcisi S, Müller C, Schmitt-Kopplin P, Schindler M, Brack-Werner R (2014) The root extract of the medicinal plant Pelargonium sidoides is a potent HIV-1 attachment inhibitor. PLoS One 9(1):e87487PubMedPubMedCentralCrossRefGoogle Scholar
  221. 221.
    Suedee A, Tewtrakul S, Panichayupakaranant P (2013) Anti-HIV-1 integrase compound from Pometia pinnata leaves. Pharm Biol 51(10):1256–1261PubMedCrossRefGoogle Scholar
  222. 222.
    Nutan, Modi M, Dezzutti CS, Kulshreshtha S, Rawat AK, Srivastava SK, Malhotra S, Verma A, Ranga U, Gupta SK (2013) Extracts from Acacia catechu suppress HIV-1 replication by inhibiting the activities of the viral protease and Tat. Virol J 10:309PubMedPubMedCentralCrossRefGoogle Scholar
  223. 223.
    Leteane MM, Ngwenya BN, Muzila M, Namushe A, Mwinga J, Musonda R, Moyo S, Mengestu YB, Abegaz BM, Andrae-Marobela K (2012) Old plants newly discovered: Cassia sieberiana D.C. and Cassia abbreviata Oliv. Oliv. root extracts inhibit in vitro HIV-1c replication in peripheral blood mononuclear cells (PBMCs) by different modes of action. J Ethnopharmacol 141(1):48–56PubMedCrossRefGoogle Scholar
  224. 224.
    Park IW, Han C, Song X, Green LA, Wang T, Liu Y, Cen C, Song X, Yang B, Chen G, He JJ (2009) Inhibition of HIV-1 entry by extracts derived from traditional Chinese medicinal herbal plants. BMC Complement Altern Med 9:29PubMedPubMedCentralCrossRefGoogle Scholar
  225. 225.
    Bobbin ML, Burnett JC, Rossi JJ (2015) RNA interference approaches for treatment of HIV-1 infection. Genome Med 7(1):50PubMedPubMedCentralCrossRefGoogle Scholar
  226. 226.
    Swaminathan G, Navas-Martín S, Martín-García J (2014) MicroRNAs and HIV-1 infection: antiviral activities and beyond. J Mol Biol 426(6):1178–1197PubMedCrossRefGoogle Scholar
  227. 227.
    Lai YT, DeStefano JJ (2012) DNA aptamers to human immunodeficiency virus reverse transcriptase selected by a primer-free SELEX method: characterization and comparison with other aptamers. Nucleic Acid Ther 22(3):162–176PubMedPubMedCentralCrossRefGoogle Scholar
  228. 228.
    Jorgensen WL (2004) The many roles of computation in drug discovery. Science 303(5665):1813–1818PubMedCrossRefGoogle Scholar
  229. 229.
    Geppert H, Vogt M, Bajorath J (2010) Current trends in ligand-based virtual screening: molecular representations, data mining methods, new application areas, and performance evaluation. J Chem Inf Model 50:205–216PubMedCrossRefGoogle Scholar
  230. 230.
    Wei Y, Li J, Chen Z, Wang F, Huang W, Hong Z, Lin J (2015) Multistage virtual screening and identification of novel HIV-1 protease inhibitors by integrating SVM, shape, pharmacophore and docking methods. Eur J Med Chem 101:409–418PubMedCrossRefGoogle Scholar
  231. 231.
    Tewtrakul S, Chaniad P, Pianwanit S, Karalai C, Ponglimanont C, Yodsaoue O (2015) Anti-HIV-1 integrase activity and molecular docking study of compounds from Caesalpinia sappan L. Phytother Res 29(5):724–729PubMedCrossRefGoogle Scholar
  232. 232.
    Ahmad M, Aslam S, Rizvi SU, Muddassar M, Ashfaq UA, Montero C, Ollinger O, Detorio M, Gardiner JM, Schinazi RF (2015) Molecular docking and antiviral activity of N-substituted benzyl/phenyl-2-(3,4-dimethyl-5,5-dioxidopyrazolo[4,3-c][1,2]benzothiazin-2(4H)-yl)acetamides. Bioorg Med Chem Lett 25(6):1348–1351PubMedCrossRefGoogle Scholar
  233. 233.
    Singh A, Yadav D, Yadav M, Dhamanage A, Kulkarni S, Singh RK (2015) Molecular modeling, synthesis and biological evaluation of N-heteroaryl compounds as reverse transcriptase inhibitors against HIV-1. Chem Biol Drug Des 85(3):336–347PubMedCrossRefGoogle Scholar
  234. 234.
    Filimonov DA, Lagunin AA, Gloriozova TA, Rudik AV, Druzhilovskii DS, Pogodin PV, Poroikov VV (2014) Prediction of the biological activity spectra of organic compounds using the PASS online web resource. Chem Heterocycl Compd 50(3):444–457CrossRefGoogle Scholar
  235. 235.
    Zhang C, Du C, Feng Z, Zhu J, Li Y (2015) Hologram quantitative structure activity relationship, docking, and molecular dynamics studies of inhibitors for CXCR4. Chem Biol Drug Des 85(2):119–136PubMedCrossRefGoogle Scholar
  236. 236.
    Corona A, Di Leva FS, Thierry S, Pescatori L, Cuzzucoli Crucitti G, Subra F, Delelis O, Esposito F, Rigogliuso G, Costi R, Cosconati S, Novellino E, Di Santo R, Tramontano E (2014) Identification of highly conserved residues involved in inhibition of HIV-1 RNase H function by diketo acid derivatives. Antimicrob Agents Chemother 58(10):6101–6110PubMedPubMedCentralCrossRefGoogle Scholar
  237. 237.
    Meleddu R, Cannas V, Distinto S, Sarais G, Del Vecchio C, Esposito F, Bianco G, Corona A, Cottiglia F, Alcaro S, Parolin C, Artese A, Scalise D, Fresta M, Arridu A, Ortuso F, Maccioni E, Tramontano E (2014) Design, synthesis, and biological evaluation of 1,3-diarylpropenones as dual inhibitors of HIV-1 reverse transcriptase. ChemMedChem 9(8):1869–1879PubMedGoogle Scholar
  238. 238.
    Song Y, Zhan P, Li X, Rai D, De Clercq E, Liu X (2013) Multivalent agents: a novel concept and preliminary practice in Anti-HIV drug discovery. Curr Med Chem 20(6):815–832PubMedGoogle Scholar
  239. 239.
    Poroikov VV, Filimonov DA, Ihlenfeldt W-D, Gloriozova TA, Lagunin AA, Borodina YV, Stepanchikova AV, Nicklaus MC (2003) PASS biological activity spectrum predictions in the enhanced open NCI database browser. J Chem Inf Comput Sci 43(1):228–236PubMedCrossRefGoogle Scholar
  240. 240.
    Liao C, Nicklaus MC (2010) Computer tools in the discovery of HIV-1 integrase inhibitors. Future Med Chem 7:1123–1140CrossRefGoogle Scholar
  241. 241.
    Alcaro S, Artese A, Ceccherini-Silberstein F, Chiarella V, Dimonte S, Ortuso F, Perno CF (2010) Computational analysis of Human Immunodeficiency Virus (HIV) Type-1 reverse transcriptase crystallographic models based on significant conserved residues found in Highly Active Antiretroviral Therapy (HAART)-treated patients. Curr Med Chem 17(4):290–308PubMedCrossRefGoogle Scholar
  242. 242.
    Kirchmair J, Distinto S, Liedl KR, Markt P, Rollinger JM, Schuster D, Spitzer GM, Wolber G (2011) Development of anti-viral agents using molecular modeling and virtual screening techniques. Infect Disord Drug Targets 11(1):64–93PubMedCrossRefGoogle Scholar
  243. 243.
    Rawal RK, Murugesan V, Katti SB (2012) Structure-activity relationship studies on clinically relevant HIV-1 NNRTIs. Curr Med Chem 19(31):5364–5380PubMedCrossRefGoogle Scholar
  244. 244.
    Hao GF, Yang SG, Yang GF (2014) Structure-based design of conformationally flexible reverse transcriptase inhibitors to combat resistant HIV. Curr Pharm Des 20(5):725–739PubMedCrossRefGoogle Scholar
  245. 245.
    Seckler JM, Leioatts N, Miao H, Grossfield A (2013) The interplay of structure and dynamics: insights from a survey of HIV-1 reverse transcriptase crystal structures. Proteins 81(10):1792–1801PubMedPubMedCentralCrossRefGoogle Scholar
  246. 246.
    Allen WJ, Balius TE, Mukherjee S, Brozell SR, Moustakas DT, Lang PT, Case DA, Kuntz ID, Rizzo RC (2015) DOCK 6: impact of new features and current docking performance. J Comput Chem 36(15):1132–1156PubMedPubMedCentralCrossRefGoogle Scholar
  247. 247.
    Tarasova OA, Urusova AF, Filimonov DA, Nicklaus MC, Zakharov AV, Poroikov VV (2015) QSAR modeling using large-scale databases: case study for HIV-1 reverse transcriptase inhibitors. J Chem Inf Model. doi: 10.1021/acs.jcim.5b00019. First published online June 5, 2015CrossRefPubMedGoogle Scholar
  248. 248.
    De Clercq E (2015) Curious discoveries in antiviral drug development: the role of serendipity. Med Res Rev 35(4):698–719PubMedCrossRefGoogle Scholar
  249. 249.
    Filimonov DA, Lagunin AA, Gloriozova TA, Gawande D, Goel R, Poroikov VV (2014) Libraries of natural and synthetic compounds as sources of novel drug-candidates. In: Chemistry of heterocyclic compounds. Modern trends, vol 1. ICSPF, Moscow. pp 464–471 (Rus)Google Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Athina Geronikaki
    • 1
  • Phaedra Eleftheriou
    • 2
  • Vladimir Poroikov
    • 3
  1. 1.Department of Medicinal Chemistry, School of PharmacyAristotle University of ThessalonikiThessalonikiGreece
  2. 2.Department of Medical Laboratory Studies, School of Health and Medical CareAlexander Technological Educational Institute of ThessalonikiThessalonikiGreece
  3. 3.Institute of Biomedical ChemistryMoscowRussia

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