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Novel Targets and Advancements in Drug Discovery: The Case of HIV-AIDS

  • Nihar Ranjan
  • Umesh Kumar
  • Sunil K. Deshmukh
Chapter

Abstract

Since the very first report of acquired immune deficiency syndrome (AIDS) in the early 1980s in the United States, a number of advancements have taken place both in the structural and functional aspects of the human immunodeficiency virus (HIV) life cycle as well as anti-HIV drug design. While new drugs have come to the market and combination therapies have increased life expectancy, resistance and viral mutations have mandated introduction of new drugs in the market. Apart from two main classes of HIV inhibitors (reverse transcriptase and protease), new inhibitors targeting fusion and integration processes have provided additional sites for therapy development. More recently inhibitors of maturation and capsid assembly as well as viral replication have been studied to provide novel anti-HIV drugs. In this chapter, we briefly discuss the HIV life cycle and describe a few of the recent endeavors made to develop new anti-HIV agents. For brevity, we provide a limited number of examples of discoveries made in the main target sites of current HIV drug design.

Keywords

Novel targets HIV Reverse transcriptase Antiviral drug 

References

  1. Ali A, Reddy GSK, Nalam MNL, Anjum SG, Cao H, Schiffer CA, Rana TM (2010) Structure-based design, synthesis, and structure activity relationship studies of HIV-1 protease inhibitors incorporating phenyloxazolidinones. J Med Chem 53(21):7699–7708CrossRefPubMedPubMedCentralGoogle Scholar
  2. Athanassiou Z, Dias RLA, Moehle K, Dobson N, Varani G, Robinson JA (2004) Structural mimicry of retroviral tat proteins by constrained beta-hairpin peptidomimetics: ligands with high affinity and selectivity for viral TAR RNA regulatory elements. J Am Chem Soc 126(22):6906–6913CrossRefPubMedGoogle Scholar
  3. Athanassiou Z, Patora K, Dias RLA, Moehle K, Robinson JA, Varani G (2007) Structure-guided peptidomimetic design leads to nanomolar beta-hairpin inhibitors of the Tat-TAR interaction of bovine immunodeficiency virus. Biochemistry 46(3):741–751CrossRefPubMedGoogle Scholar
  4. Billamboz M, Suchaud V, Bailly F, Lion C, Andréola M, Christ F, Debyser Z, Cotelle P (2016) 2-hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs) as human immunodeficiency virus type 1 integrase inhibitors: influence of the alkylcarboxamide substitution of position 4. Eur J Med Chem 117:256–268CrossRefPubMedGoogle Scholar
  5. Bungard CJ, Williams PD, Ballard JE, Bennett DJ, Beaulieu C, Bahnck-Teets C, Carroll SS, Chang RK, Dubost DC, Fay JF, Diamond TL, Greshock TJ, Hao L, Holloway MK, Felock PJ, Gesell JJ, Su HP, Manikowski JJ, McKay DJ, Miller M, Min X, Molinaro C, Moradei OM, Nantermet PG, Nadeau C, Sanchez RI, Satyanarayana T, Shipe WD, Singh SK, Truong VL, Vijayasaradhi S, Wiscount CM, Vacca JP, Crane SN, McCauley JA (2016) Discovery of MK-8718, an HIV protease inhibitor containing a novel morpholine aspartate binding group. ACS Med Chem Lett 7(7):702–707CrossRefPubMedGoogle Scholar
  6. Chong P, Sebahar P, Youngman M, Garrido D, Zhang H, Stewart EL, Nolte RT, Wang L, Ferris RG, Edelstein M, Weaver K, Mathis A, Peat A (2012) Rational design of potent non-nucleoside inhibitors of HIV-1 reverse transcriptase. J Med Chem 55(23):10601–10609CrossRefPubMedGoogle Scholar
  7. Dassonneville L, Hamy F, Colson P, Houssier C, Bailly C (1997) Binding of hoechst 33258 to the TAR RNA of HIV-1. Recognition of a pyrimidine bulge-dependent structure. Nucleic Acids Res 25(22):4487–4492CrossRefPubMedPubMedCentralGoogle Scholar
  8. Dogo-Isonagie C, Lee S, Lohith K, Liu H, Mandadapu S. R, Lusvarghi S, O’Connor RD, Bewley CA (2016) Design and synthesis of small molecule-sulfotyrosine mimetics that inhibit HIV-1 entry. Bioorg Med Chem 24(8): 1718–1728.Google Scholar
  9. Dong M, Lu L, Li H, Wang X, Lu H, Jiang S, Dai QY (2012) Design, synthesis, and biological activity of novel 1,4-disubstituted piperidine/piperazine derivatives as CCR5 antagonist-based HIV-1 entry inhibitors. Bioorg Med Chem Lett 22(9):3284–3286CrossRefPubMedGoogle Scholar
  10. Ganguly AK, Alluri SS, Wang C, Antropow A, White A, Caroccia D, Biswas D, Kang E, Zhang LK, Carroll SS, Burlein C, Fay J, Orth P, Strickland C (2014) Structural optimization of cyclic sulfonamide based novel HIV-1 protease inhibitors to picomolar affinities guided by X-ray crystallographic analysis. Tetrahedron 70(18):2894–2904CrossRefGoogle Scholar
  11. Gao B, Zhang C, Yin Y, Tang L, Liu Z (2011) Design and synthesis of potent HIV-1 protease inhibitors incorporating hydroxyprolinamides as novel P2 ligands. Bioorg Med Chem Lett 21(12):3730–3733CrossRefPubMedGoogle Scholar
  12. Ghosh AK, Osswald HL, Prato G (2016) Recent progress in the development of HIV-1 protease inhibitors for the treatment of HIV/AIDS. J Med Chem 59(11):5172–5208CrossRefPubMedGoogle Scholar
  13. Gu W, Ip DT, Liu S, Chan JH, Wang Y, Zhang X, Zheng YT, Wan DC (2014) 1,4-bis(5-(naphthalen-1-yl) thiophen-2-yl)naphthalene, a small molecule, functions as a novel anti-HIV-1 inhibitor targeting the interaction between integrase and cellular lens epithelium-derived growth factor. Chem Biol Interact 213:21–27CrossRefPubMedGoogle Scholar
  14. Hughes JP, Rees S, Kalindjian SB, Philpott KL (2010) Principles of early drug discovery. Br J Pharmacol 162(6):1239–1249CrossRefGoogle Scholar
  15. Kankanala J, Kirby KA, Liu F, Miller L, Nagy E, Wilson DJ, Parniak MA, Sarafianos SG, Wang Z (2016) Design, synthesis, and biological evaluations of hydroxypyridonecarboxylic acids as inhibitors of HIV reverse transcriptase associated RNase H. J Med Chem 59(10):5051–5062CrossRefPubMedPubMedCentralGoogle Scholar
  16. Kim J, Lee D, Park C, So W, Jo M, Ok T, Kwon J, Kong S, Jo S, Kim Y, Choi J, Kim HC, Ko Y, Choi I, Park Y, Yoon J, Ju MK, Kim J, Han SJ, Kim TH, Cechetto J, Nam J, Sommer P, Liuzzi M, Lee J, No Z (2012) Discovery of phenylaminopyridine derivatives as novel HIV-1 non-nucleoside reverse transcriptase inhibitors. ACS Med Chem Lett 3(8):678–682CrossRefPubMedPubMedCentralGoogle Scholar
  17. Kumar S, Kellish P, Robinson WE, Wang D, Appella DH, Arya DP (2012) Click dimers to target HIV TAR RNA conformation. Biochemistry 51:2331–2347CrossRefPubMedPubMedCentralGoogle Scholar
  18. Kumar S, Ranjan N, Kellish P, Gong C, Watkins D, Arya DP (2016) Multivalency in the recognition and antagonism of a HIV TAR RNA-TAT assembly using an aminoglycoside benzimidazole scaffold. Org Biomol Chem 14(6):2052–2056CrossRefPubMedPubMedCentralGoogle Scholar
  19. Liu Z, Swidorski JJ, Nowicka-Sans B, Terry B, Protack T, Lin Z, Samanta H, Zhang S, Li Z, Parker DD, Rahematpura S, Jenkins S, Beno BR, Krystal M, Meanwell NA, Dicker IB, Regueiro-Ren A (2016) C-3 benzoic acid derivatives of C-3 deoxybetulinic acid and deoxybetulin as HIV-1 maturation inhibitors. Bioorg Med Chem 24(8):1757–1770CrossRefPubMedGoogle Scholar
  20. Luedtke NW, Tor Y (2003) Fluorescence-based methods for evaluating the RNA affinity and specificity of HIV-1 rev? RRE inhibitors. Biopolymers 70(1):103–119CrossRefPubMedGoogle Scholar
  21. Macarron R (2006) Critical review of the role of HTS in drug discovery. Drug Discov Today 11(7):277–279CrossRefPubMedGoogle Scholar
  22. Mayr LM, Bojanic D (2009) Novel trends in high-throughput screening. Curr Opin Pharmacol; Anti-infect/New Technol 9(5):580–588CrossRefGoogle Scholar
  23. Mizuguchi T, Harada S, Miura T, Ohashi N, Narumi T, Mori H, Irahara Y, Yamada Y, Nomura W, Matsushita S, Yoshimura K, Tamamura H (2016) A minimally cytotoxic CD4 mimic as an HIV entry inhibitor. Bioorg Med Chem Lett 26(2):397–400CrossRefPubMedGoogle Scholar
  24. Munos B (2009) Lessons from 60 years of pharmaceutical innovation. Nat Rev Drug Discov 8(12):959–968CrossRefPubMedGoogle Scholar
  25. O’Hara BM, Olson WC (2002) HIV entry inhibitors in clinical development. Curr Opin Pharmacol 2(5):523–528CrossRefPubMedGoogle Scholar
  26. Ohrngren P, Wu X, Persson M, Ekegren JK, Wallberg H, Vrang L, Rosenquist A, Samuelsson B, Unge T, Larhed M (2011) HIV-1 protease inhibitors with a tertiary alcohol containing transition-state mimic and various P2 and P1prime or minute substituents. Med Chem Commun 2(8):701–709CrossRefGoogle Scholar
  27. Patel RV, Park SW (2015) Pyrroloaryls and pyrroloheteroaryls: inhibitors of the HIV fusion/attachment, reverse transcriptase and integrase. Bioorg Med Chem 23(17):5247–5263CrossRefPubMedGoogle Scholar
  28. Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Lindborg SR, Schacht AL (2010) How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat Rev Drug Discov 9(3):203–214PubMedGoogle Scholar
  29. Peytou V, Condom R, Patino N, Guedj R, Aubertin A, Gelus N, Bailly C, Terreux R, Cabrol-Bass D (1999) Synthesis and antiviral activity of ethidium-arginine conjugates directed against the TAR RNA of HIV-1. J Med Chem 42(20):4042–4053CrossRefPubMedGoogle Scholar
  30. Qiu X, Zhao G, Tang L, Liu Z (2014) Design and synthesis of highly potent HIV-1 protease inhibitors with novel isosorbide-derived P2 ligands. Bioorg Med Chem Lett 24(11):2465–2468CrossRefPubMedGoogle Scholar
  31. Ramana LN, Anand AR, Sethuraman S, Krishnan UM (2014) Targeting strategies for delivery of anti-HIV drugs. J Control Release 192:271–283CrossRefPubMedGoogle Scholar
  32. Ranjan N, Kumar S, Watkins D, Wang D, Appella DH, Arya DP (2013) Recognition of HIV-TAR RNA using neomycin–benzimidazole conjugates. Bioorg Med Chem Lett 23(20):5689–5693CrossRefPubMedPubMedCentralGoogle Scholar
  33. Swidorski JJ, Liu Z, Yin Z, Wang T, Carini DJ, Rahematpura S, Zheng M, Johnson K, Zhang S, Lin PF, Parker DD, Li W, Meanwell NA, Hamann LG, Regueiro-Ren A (2016) Inhibitors of HIV-1 attachment: the discovery and structure–activity relationships of tetrahydroisoquinolines as replacements for the piperazine benzamide in the 3-glyoxylyl 6-azaindole pharmacophore. Bioorg Med Chem Lett 26(1):160–167CrossRefPubMedGoogle Scholar
  34. Tang J, Maddali K, Dreis CD, Sham YY, Vince R, Pommier Y, Wang Z (2011) N-3 hydroxylation of pyrimidine-2,4-diones yields dual inhibitors of HIV reverse transcriptase and integrase. ACS Med Chem Lett 2(1):63–67CrossRefPubMedGoogle Scholar
  35. Tremblay M, Bonneau P, Bousquet Y, DeRoy P, Duan J, Duplessis M, Gagnon A, Garneau M, Goudreau N, Guse I, Hucke O, Kawai SH, Lemke CT, Mason SW, Simoneau B, Surprenant S, Titolo S, Yoakim C (2012) Inhibition of HIV-1 capsid assembly: optimization of the antiviral potency by site selective modifications at N1, C2 and C16 of a 5-(5-furan-2-yl-pyrazol-1-yl)-1H-benzimidazole scaffold. Bioorg Med Chem Lett 22(24):7512–7517CrossRefPubMedGoogle Scholar
  36. UNAIDS (2016) Global AIDS update, 2016. Retrieved June 29, 2016, from http://www.unaids.org/en/resources/documents/2016/Global-AIDS-update-2016
  37. Velthuisen EJ, Johns BA, Temelkoff DP, Brown KW, Danehower SC (2016) The design of 8-hydroxyquinoline tetracyclic lactams as HIV-1 integrase strand transfer inhibitors. Eur J Med Chem 117:99–112CrossRefPubMedGoogle Scholar
  38. Wan Z, Yao J, Mao T, Wang X, Wang H, Chen W, Yin H, Chen FE, De Clercq E, Daelemans D, Pannecouque C (2015) Pyrimidine sulfonylacetanilides with improved potency against key mutant viruses of HIV-1 by specific targeting of a highly conserved residue. Eur J Med Chem 102:215–222CrossRefPubMedGoogle Scholar
  39. Wang S, Huber PW, Cui M, Czarnik AW, Mei H (1998) Binding of neomycin to the TAR element of HIV-1 RNA induces dissociation of tat protein by an allosteric mechanism. Biochemistry 37(16):5549–5557CrossRefPubMedGoogle Scholar
  40. Wannberg J, Sabnis YA, Vrang L, Samuelsson B, Karlén A, Hallberg A, Larhed M (2006) A new structural theme in C2-symmetric HIV-1 protease inhibitors: ortho-substituted P1/P1′ side chains. Bioorg Med Chem 14(15):5303–5315CrossRefPubMedGoogle Scholar
  41. Wu B, Tang J, Wilson DJ, Huber AD, Casey MC, Ji J, Kankanala J, Xie J, Sarafianos SG, Wang Z (2016) 3-hydroxypyrimidine-2,4-dione-5-N-benzylcarboxamides potently inhibit HIV-1 integrase and RNase H. J Med Chem 59(13):6136–6148CrossRefPubMedGoogle Scholar
  42. Yang J, Chen W, Kang D, Lu X, Li X, Liu Z et al (2016) Design, synthesis and anti-HIV evaluation of novel diarylpyridine derivatives targeting the entrance channel of NNRTI binding pocket. Eur J Med Chem 109:294–304CrossRefPubMedGoogle Scholar
  43. Zhan P, Pannecouque C, De Clercq E, Liu X (2016) Anti-HIV drug discovery and development: current innovations and future trends. J Med Chem 59(7):2849–2878CrossRefPubMedGoogle Scholar
  44. Zhao XZ, Smith SJ, Maskell DP, Metifiot M, Pye VE, Fesen K et al (2016) HIV-1 integrase strand transfer inhibitors with reduced susceptibility to drug resistant mutant integrases. ACS Chem Biol 11(4):1074–1081CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  1. 1.TERI-Deakin Nanobiotechnology CenterThe Energy and Resources Institute, TERI GramGurugramIndia

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