Introduction

Infectious diseases have been recognized by humankind since the very beginning of civilization. Viruses are sub-vital elements that are considered among the most important human pathogenesis (Saxena et al., 2010). Viruses are known to cause severe infectious diseases with a high mortality rate (Lou et al., 2014; Pour et al. 2019). The 21st century is marked by major epidemics, including ones that even can be considered pandemics, caused by ancient diseases such as cholera, plague, and yellow fever, as well as newer diseases such as severe acute respiratory syndrome (SARS), Ebola, Zika, Middle East Respiratory Syndrome (MERS), HIV (although technically endemic), influenza A (H1N1) pdm/09 and most recently COVID-19 (Ong et al. 2020). Among the mentioned infections, viral infections have attracted more attention due to the high mortality rate of the recent COVID-19 pandemic. Therefore, the discovery and design of antiviral medications seem vital. Antiviral therapeutics can be categorized into three main categories: virucides, immunomodulatory agents, and antivirals. Virucides are agents or physical factors that are capable of neutralizing or destroying a virus; for example, organic solvents, detergents, and ultraviolet light (UV). Immunomodulatory drugs consist of agents that augment the host’s response to infections such as antibodies, cytokines, interferons, hormones, antigens, therapeutic vaccines, corticosteroids, and certain neutraceuticals. Antivirals are the molecules that prevent viral proliferation by targeting a particular stage of their life cycles. These drugs might have a limited spectrum of activity, and although may not be as effective on latent viruses, they usually act selectively (Saxena et al. 2009; Saxena et al., 2010).

The uses of antiviral agents are progressing nowadays along with the development of vaccines to effectively control viral diseases. The main goals of the antiviral agents are to minimize the inflicted damage to the host cell and eradicate or limit fatal viral diseases. Antiviral drugs, not only penetrate and disrupt the virus, but they can also negatively impact the normal physiological pathways in the host. Antiviral agents also have a narrower therapeutic index when compared to antibacterial drugs. Nephrotoxicity is the primary adverse reaction of antiviral drugs in humans and animals (Bule et al. 2019).

Since the survivability of the virus depends on the host cell, the selection of a target for the design of effective and safe antiviral drugs without harming the host cell is quite a challenging process (Agarwal and Gabrani 2020). In addition, viruses have employed many devious strategies to escape host immune responses and consequently, have been able to plague human health throughout history. Fighting viral infections through vaccines or antiviral drugs or both is always a challenge. Furthermore, discovering and developing new vaccines is normally challenging and time-consuming (Mahmoud, 2016). Even at times when successful strategies are discovered and used, the high rate of genetic change shown by many viruses, especially RNA viruses, often leads to drug resistance or vaccine escape (Blair and Cox 2016). Viruses, including SARS-CoV, SARS-COV2, and influenza, can mutate quickly, as a result, they reduce the efficacy of developed vaccines and targeted antiviral medicines (Anderson and Reiter 2020). Despite the quick progress made in human healthcare, there are just a few virucidal and antiviral therapies that are sufficiently efficient. The increasing reports of the emergence, and re-emergence of viral epidemics (Boas et al., 2019), safety and efficacy limitations and soaring costs, and also the adverse effects of synthetic antiviral drugs, escalate the need to identify new, effective, and safe alternatives to fight viral diseases (Pour et al. 2019).

This article explores one of the promising and emerging fields of ″peptide-based therapeutics″ by namely Antimicrobial peptides (AMPs) against a vast number of microbes i.e., bacteria, fungi, parasites, viruses (Agarwal and Gabrani 2020; Mohan et al., 2010). Over the past several years, a lot of scientific efforts have been made to identify novel and potential peptide-based therapeutics using different advanced technologies. Thus, more than 60 approved peptide drugs are available for sale in the markets of the United States, Europe, Japan, and some Asian countries. Moreover, the number of peptide drugs that are undergoing clinical trials is rising gradually every year. Unfortunately, merely a few therapeutic agents are available for viruses such as human immunodeficiency virus (HIV), hepatitis virus, herpes simplex virus (HSV), and influenza virus (Agarwal and Gabrani 2020). In this review, we will elaborate on some of the progress in peptide and protein-based antiviral drugs focusing on the most important related patents, FDA-approved peptide drugs, and AVPs that are going through the clinical trial phases.

Antivirals Peptides and Other Peptide Related Antivirals

AMPs, a diverse group of bioactive small peptides act as a part of the body’s first line of defense against pathogen inactivation. AMPs will be a better choice if employed as an antiviral agent because they occur naturally, and are an innate host defense mechanism (Maiti, 2020). AMPs with antiviral activity or antiviral peptides (AVPs) have turned into a research hotspot and already show tremendous potential to become pharmaceutically available antiviral medicines. AVPs have shown great potential in inhibiting viruses by rupturing the viral capsid, directly inhibiting the virus, and targeting various stages of the viral life cycles (Dutta 2020; Feng et al. 2020; Rider et al. 2011). Some disadvantages of AMPs such as expensive synthesis, time-consuming production, high degradability in some physiological conditions, low stability, immunogenicity, and cytotoxicity have limited their use in the clinic (Kang et al., 2014; Rinanda 2019).

To overcome the above-mentioned limitations, in silico approaches are cost-effective strategies to design and modify AMPs (Rinanda 2019). In silico study is a logical extension of in vitro method, which simulates biological and physiological processes in a computer (Rinanda 2019). Advanced strategies of rational design together with computational methods are used for the development of more economical and powerful AMPs as potential next-generation antimicrobials (Fjell et al., 2012). The rational design of new drugs has been turned into a major area in medicinal chemistry, aiming at creating pharmaceuticals with greater specificity against microorganisms, together with reduced side effects. In this context, several computational tools are developed to design AMP variants; like empirical methods and machine learning algorithms, as also stochastic approaches. Amongst the machine learning strategies, a particular focus is given to the quantitative structure-activity relationship (QSAR) model, which utilizes physicochemical descriptors to predict the biological activity of peptides from their amino acid sequences (Cardoso et al., 2020).

An example of antiviral peptides that can be designed by the above-mentioned computer-based methods is killer peptides (KPs). Such biologically active peptides subtype, are among a larger group defined as cryptids. The mentioned group can be derived from the proteolytic cleavage of physiological proteins. Cryptids might show a broad spectrum of biological activities, distinct from those of the precursor proteins. KPs are the leading compounds of a group of antibody-derived fragments vested with various biological activities. KPs have exhibited potent activity against many different viruses such as HIV and influenza, by different action mechanisms (Sala et al., 2018).

The AVPs can be acquired via different approaches: 1- screening of natural sources, 2- design by computational approaches, and 3- high-throughput screening of peptide libraries (Agarwal and Gabrani 2020).

The naturally occurring AVPs are amphipathic and cationic and usually carry a net positive charge (Bulet et al., 2004). It has been proven that hydrophobicity seems to be an effective pattern for many antiviral molecules that target enveloped viruses such as RSVs (Badani et al., 2014). These AVPs can be derived from different sources such as plants, bacteria, animals, and might possess various action mechanisms (Skalickova et al., 2015; Wang, 2012).

Natural antimicrobial peptides have been intensively altered through synthetic chemistry for the purpose of meeting the requirements of potential therapeutic drugs, consequently, increasing the structural diversity more than before (Mojsoska & Jenssen, 2015). Methods are founded based on in vitro display approach, offering genetically encoded peptides with superior quality and high affinity to their targets. Among these methods, phage display, mRNA display, ribosome display, and yeast display are the most common technologies to generate peptides (Linciano et al., 2019; Nevola & Giralt, 2015).

The computer-assisted drug design is based on understanding the structural and functional aspects of the viral machinery. The rational knowledge of the viral proteins and the interactors/cellular partners aids with selecting the target protein. Peptides can be identified computationally; via in silico screening through molecular docking. A docking program foresees the target site, usually identified as a pocket or protrusion with hydrogen bond donors and acceptors, hydrophobic characteristics, and different molecular shapes. Next, a peptide library docked with these pockets would give rise to the highest binding peptide (Agarwal and Gabrani 2020; Nevola & Giralt, 2015).

Many online databases are available that contain useful information regarding experimentally tested antiviral peptides. The antiviral peptide database (AVPdp)(Agarwal and Gabrani 2020; Thakur et al., 2012) with 2683 peptides by December 2020 is one of the more important databases (http://crdd.osdd.net/servers/avpdb/index.php).

Many instances of antimicrobial peptides (AMPs) have displayed inhibitory activities against HSV infection. Their antiviral mechanism includes cellular target and viral inactivation (magainin, cecropin, melittin, LL-37, and brevinin-1), interaction with HSV membrane/glycoprotein, and cellular targets excluding heparan sulfate (human and rabbit defensins), viral inactivating effects (tachyplesin and protegrin), bound to gB protein, and blocked HSV-1 attachment (ϴ-defensin), and block HSV entry into Vero cells (lactoferrin and lactoferricin) (Hong et al., 2014).

Mucroporin is the first cationic host defense peptide from the scorpion venom Lychas mucronatus, which can effectively kill bacteria, especially gram-positive bacteria. The optimized design of mucroporin-M1 by amino acid substitution resulted in the hampering of gram-positive bacteria at low concentrations and increased the hampering of antibiotic-resistant pathogens (Li et al., 2011). Also, mucroporin-M1 exhibited to be virucidal activity against the measles, SARS-CoV, and influenza H5N1 viruses, and it restrained HBV replication in vitro and in vivo (Li et al., 2011; Zhao et al., 2012). Huimin Yan et al. showed that a novel α-helical peptide Hp1090 from scorpion venom can hamper HCV replication and prevents the initiation of HCV infection (Yan et al., 2011).

The design and synthesis of peptide mimics (peptidomimetics) have been developed to mimic the structure, function, and mode of action of host-defense AMPs (Méndez-Samperio, 2014). Many instances of peptidomimetics are reported, most of which were synthesized via altered solid-phase peptide synthesis methods. Some examples of strategies for the production of peptidomimetics include using D-amino acid substitutions, with reduced and functionalized amide bonds, peptoids, urea peptidomimetics, peptide sulfonamides, oligocarbamates, partial or full retro-Inverso peptides, azapeptides, β-peptides, and N-modified peptides. (VanPatten et al. 2020).

Antimicrobial peptidomimetics are superior to AMPs in several aspects, including enhanced stability, cell specificity, enhanced receptor affinity and selectivity, improved bioavailability, better tolerability, and enhanced chemo-diversity (Lachowicz et al., 2020; Lenci & Trabocchi, 2020; Méndez-Samperio, 2014). Additionally, the flexibility in the synthesis of these molecules allows fast structure modifications for the creation of novel antimicrobial peptidomimetics, with particular pharmacological properties (Méndez-Samperio, 2014).

Recent Patents in Antiviral Peptides and Other Peptide-Related Antivirals

Simultaneously, with the emergence of studies about the design and fabrication of antiviral peptides and related structures such as peptidomimetics, the patents in this field, fabrication methods, and modification have also been recorded recently. Some most significant patents and their applications in this field during 2000–2020 are introduced in Table 1. These patents presented antiviral activity against various viruses such as HIV, Rift Valley Fever Virus Peptides (RVFV), influenza A, B, and Ebola viruses.

Table 1 Some of the most important patents (2000–2020) in antiviral peptides and peptide-related antivirals
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FDA Approved AVPs and Other Peptide Related Antivirals

More than 60 approved peptide drugs are available for selling in the market countries including the United States, Europe, Japan, and some Asian countries. Moreover, the number of peptide drugs undergoing clinical trials is rising slowly year by year. For example, over 400 peptides are under clinical trial phases, more than 150 are in active clinical development, and a further 260 have been tested in human clinical trials. The peptide-based antiviral therapeutics have been confirmed for the human immunodeficiency virus (HIV), Influenza virus, and hepatitis virus (Agarwal and Gabrani 2020; Findlay et al., 2013; Lau & Dunn, 2018).

Enfuvirtide (also known as T-20) is the first FDA- approved viral peptide inhibitor. It is a synthetic peptide with 36 residues that act against HIV. Enfuvirtide prevents the fusion of the HR1 domain to HR2 throughout HIV infection (Lalezari et al., 2003; Matthews et al., 2004; Teissier et al., 2011). The first generation of fusion inhibitors, Enfuvirtide, nSJ-2176, and C34, are peptidomimetics of the HR2 domain and act by competitively binding to HR1 to prevent the interaction among HR-1 and HR-2, consequently blocking the formation of the 6-helix bundle and fusion of HIV-1 along with the extracellular membrane of host cells (Berkhout et al., 2012). Enfuvirtide has minimal systemic toxicity, but long-term use of it leads to the frequent occurrence of painful injection site reactions (Henrich & Kuritzkes, 2013).

Boceprevir and Telaprevir are synthetic peptides against the hepatitis C virus (HCV) and were approved by the FDA in 2011. The peptides act on a protease inhibitor called NS3/4 and interfere with viral replication (De Clercq & Li, 2016; Divyashree et al., 2020).

There are nine peptidomimetic drugs on the market for the treatment of AIDS (Acquired immunodeficiency syndrome), and at least four in clinical development for the treatment of HCV infections (Tsantrizos, 2008).

A peptidomimetic called Saquinavir acts as a protease inhibitor for HIV-1 (De Clercq, 2009b). This molecule carries a hydroxy ethylene scaffold and mimics the typical peptide bond(but unlike the typical peptide bond, it isn’t broken by HIV-1 protease) (De Clercq, 2009a).

Recently, with the outbreak of the COVID-19 pandemic, many antiviral peptides and peptidomimetics against SARS-CoV-2 have been reported (Mousavi Maleki et al., 2021). Various therapeutic agents rapidly taken into clinical trials are mainly based on available drugs with non-specific antiviral activities or compounds pharmacologically speculated to be effective in increasing the overall clinical outcome of COVID-19 patients (Mahendran et al., 2020). To date, no peptide antiviral drug for COVID-19 has entered the clinical trial. However, some researchers have recommended some FDA-approved peptide drugs for clinical trials of COVID-19 through virtual screenings and in silico drug repurposing methods. Madanchi et al., in one of these studies, showed that the enfuvirtide could inhibit SARS-CoV2 entry into the host cell with great potency and recommended it for COVID-19 clinical trials (Ahmadi et al., 2022). FDA-approved peptide-like small molecules, amino acid-like derivatives, and peptidomimetics such as remdesivir and lopinavir have been utilized in COVID-19 clinical trials and even in its treatment. The FDA-approved AVPs and other related peptide structures (from https://go.drugbank.com/drugs) are reported in Table 2.

Table 2 Category, application and mechanism actions of some FDA approved AVPs, peptidomimetics, peptide-like structures, small molecules and amino acid-like derivatives
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Conclusion

Limitations of available medications for treating the many viral infections, the emergence of problematic resistance to these drugs, and the lack of effective antiviral vaccines against the new mutant strains have led to researchers finding novel and substitute therapeutics. Here, we reported the patents and FDA-approved drugs based on AVPs, peptidomimetics, and peptide-like structures that have good potential for use as new antiviral agents against many viral infections. In this article, some patents in antiviral peptides, peptidomimetics, and FDA-approved peptides have been collected through extensive studies in order to raise awareness of their antiviral potential. Our study showed that many of these peptides and peptidomimetics can be used against emerging viruses such as SARS-CoV, MERS-CoV, and SARS-CoV-2.