key: cord-1051388-gxauv4my
authors: Madhavan, Maya; AlOmair, Lamya Abdulaziz; KS, Deepthi; Mustafa, Sabeena
title: Exploring peptide studies related to SARS-CoV to accelerate the development of novel therapeutic and prophylactic solutions against COVID-19
date: 2021-07-03
journal: J Infect Public Health
DOI: 10.1016/j.jiph.2021.06.017
sha: 0cdf7d8efdb5f3446b2bace5d42a04bab634a1d7
doc_id: 1051388
cord_uid: gxauv4my

Recent advances in peptide research revolutionized therapeutic discoveries for various infectious diseases. In view of the ongoing threat of the COVID-19 pandemic, there is an urgent need to develop potential therapeutic options. Intense and accomplishing research is being carried out to develop broad-spectrum vaccines and treatment options for corona viruses, due to the risk of recurrent infection by the existing strains or pandemic outbreaks by new mutant strains. Developing a novel medicine is costly and time consuming, which increases the value of repurposing existing therapies. Since, SARS-CoV-2 shares significant genomic homology with SARS-CoV, we have summarized various peptides identified against SARS-CoV using in silico and molecular studies and also the peptides effective against SARS-CoV-2. Dissecting the molecular mechanisms underlying viral infection could yield fundamental insights in the discovery of new antiviral agents, targeting viral proteins or host factors. We postulate that these peptides can serve as effective components for therapeutic options against SARS-CoV-2, supporting clinical scientists globally in selectively identifying and testing the therapeutic and prophylactic agents for COVID-19 treatment. In addition, we also summarized the latest updates on peptide therapeutics against SARS-CoV-2.

with SARS and MERS (Ganesh et al., 2021) In the fight against coronaviruses, scientists developed three strategies for developing new drugs (Zumla et al., 2016) . The first strategy is to test existing broad-spectrum antivirals (Chan et al., 2013) .

Though such inhibitors have certain advantages such as clarity in terms of their metabolic characteristics, dosages used, potential efficacy, and side effects, their spectrum is too broad. The second strategy is high-throughput screening of existing molecular databases to screen for molecules that may have a therapeutic effect on coronaviruses (de Wilde et al., 2014; Dyall et al., 2014) . The third strategy is to develop new targeted drugs, directly based on the genomic information and pathological characteristics of different coronaviruses. Based on these observations, we accumulated research findings related to a specific class of therapeutic options, the peptide therapeutics and their molecular mechanisms. The compilation of publications described in this review provides an overview of the use of peptide therapeutics developed against SARS-CoV, which could be repurposed for SARS-CoV-2, as well as an update of the peptides already developed against SARS-CoV-2. However, wet lab and clinical studies are necessary to completely understand SARS-CoV-2 infection and to improve the development of these potential therapeutic options.

We performed a literature search on the Web of Science (ISI), PubMed, Embase, Medline, and Scopus databases with keywords such as SARS-CoV, 2019-nCoV, SARS-CoV-2, peptides, vaccines, and related words, for example, peptide sequences, entry peptides, and fusion peptides. All peer reviewed research and review publications, and patent studies published in the English language from 2003-2021 were considered. The titles and abstracts of the publications were reviewed by two authors.

J o u r n a l P r e -p r o o f

Publications focusing on the peptides useful in terms of SARS-CoV and SARS-CoV-2 were included.

Priority was given to publications related to three categories such as peptides identified in silico, evaluated with wet lab techniques, patented or in clinical trials.

Publications with only an abstract available were excluded from this review. Some publications were also excluded because their focus was SARS and SARS-CoV-2, without any development of therapy or peptides studies.

Data from the publications were extracted independently by two authors and entered in a table. The title and abstract of the publications which included domains such as mechanism of action, source and sequence of peptides, proposed use were reviewed. The Mendeley library was used to import citations from all the databases. Duplicate citations were removed.

Existing antiviral drugs have specific limitations, including insufficient activity, the development of resistance, safety and efficacy issues and side effects (Mohammadi Pour et al., 2019) . Small-molecule inhibitors are often less effective at disrupting extended protein binding interfaces (Smith and Gestwicki, 2012) . There is an increased interest in peptides in the pharmaceutical industry. Peptidebased drugs are a superior choice compared to small molecule drugs due to their specificity, efficiency, low molecular weight, lower toxicity and low side effects. These are synthetically accessible and can be stabilized by chemical modifications. Peptides and peptidomimetics are widely accepted because of their applications in chemical biology (Cretich et al., 2019) . Peptides inhibit protein-protein interactions and mimic a protein surface to effectively compete for binding (Cunningham et al., 2017) . Peptide drugs have several disadvantages, including instability, susceptibility to hydrolysis and oxidation, a short half-life, and low membrane permeability (Di, 2015) . There are currently more than 400 peptide based drugs in clinical development, with over 60 approved for clinical use (Lee et al., 2019) .

Literature also suggests possibilities for epitope-based vaccine screening, based on the protein motif regions, making use of peptide studies (Madhavan and Mustafa, 2020) . However, no effective peptidebased drugs are currently available against SARS-CoV-2. Antiviral peptides (AVPs) could represent a potential class of antiviral agents against SARS-CoV-2 (Chowdhury et al., 2020) . AVPs are of special interest due to their higher efficacy in inhibiting viral J o u r n a l P r e -p r o o f infection by targeting various stages of the viral life cycle (Ahmed et al., 2019) . AVPs inhibit viral replication at the stages of adsorption, viral penetration, endosomal escape, viral uncoating, viral genome replication and release of mature virions. (Vilas Boas et al., 2019) . Studies related to natural and biological sources and computational approaches, such as high-throughput screening, are supportive in identifying a promising AVP (Agarwal and Gabrani, 2020) . In our previous studies, we identified seven antimicrobial peptides (AMPs) that could serve as therapeutic components for MERS (Mustafa et al., 2019) . The various strategies and opportunities available for peptide therapeutics have been reviewed in detail by Fosgerau et al. (Fosgerau and Hoffmann, 2015) . The feasibility of developing effective therapeutic agents against MERS-CoV by repurposing existing and clinically approved anti-viral peptide drugs has been proposed (Mustafa et al., 2018) . The existing antivirals and knowledge gained from the SARS and MERS outbreaks offer the easiest and fastest route to manage the current coronavirus epidemic (Guy et al., 2020; Harrison, 2020) .

The relevance of using peptides as therapeutic options for COVID-19 have been reviewed by several authors (Khavinson et al., 2020; Mousavi Maleki et al., 2021) . Virus-based and host-based drug repurposing perspectives for coronaviruses, in general and specifically for SARS-CoV-2, have been reviewed by Cherian et al. (Cherian et al., 2020) . The significance of repurposing drugs for SARS-CoV-2 are highlighted by many authors Elfiky, 2020; Li and De Clercq, 2020; Zhou et al., 2020) . As it is evident that drug repurposing is a valid alternative for finding therapeutic solutions for COVID-19, we emphasize the importance of using peptides as anti-SARS-CoV-2 components. We present a comprehensive review of the peptides with therapeutic and prophylactic potential in SARS-CoV that could be repurposed for SARS-CoV-2, in addition to the peptides identified as effective against SARS-CoV-2. As we discuss in Table 1 , 2 and 3, it is evident that significant progress has been made in this sector, since the discovery of SARS-CoV.

Potential anti-coronavirus therapies can be divided in two categories depending on the target, acting on the viral factors or on the host factors or immune system. Based on the mechanism of action, we classified potential peptide therapeutics to combat SARS-CoV-2 in three categories, including virus entry/fusion blockers, virus replication blockers and immune modulators..

The SARS-CoV spike (S) protein, a surface glycoprotein, mediates coronavirus entry into receptorbearing cells by binding to the human angiotensin-converting enzyme 2 (hACE2) receptor (Xia et al., 2019 ). Lu et al performed bioinformatics analysis to identify peptides containing relevant B cell J o u r n a l P r e -p r o o f epitopes within the S protein of SARS-CoV which has the potential for application in the diagnosis (Lu et al., 2005) . RBD in the S1 subunit of the spike protein is a target for the development of virus attachment inhibitors, neutralizing antibodies, and vaccines (Tai et al., 2020) . Barh et al. have identified certain potential peptides to block the SARS-CoV-2 spike RBD (Barh, Tiwari, Silva Andrade, Giovanetti, Kumavath, Ghosh, Góes-Neto, Alcantara, Azevedo, 2020) . They designed ACE2 sequence based peptides after identifying the key residues interacting with the spike RBD using bioinformatics approaches. The α-helices extracted from the protease domain of ACE2 were used to design peptide inhibitors against SARS-CoV-2 (Han and Král, 2020) . S1 of RBD directly binds to the peptidase domain (PD) of ACE2. A 23-mer peptide fragment of the ACE2 PD α1 helix has been synthesized and named as SBP1, which is capable of blocking the SARS-CoV-2 spike protein interacting with ACE2 .

The coronavirus spike proteins belong to class I fusion proteins, and are characterized by the existence of two heptad repeat (HR) regions, HR1 and HR2 (Xu et al., 2004) . As soon as the S protein binds to the ACE2 receptor on the target cell, the heptad repeats interact to form a six helical bundle which is a critical and conserved mechanism for viral fusion and entry, and is shared by all coronaviruses. Hence so many attempts have been made at discovering fusion inhibitors that could act as therapeutics addressing CoV infections. A look at the sequence alignment of the HR1 and HR2 regions between SARS-CoV and SARS-CoV-2 show 92.6% and 100% sequence homology respectively, suggesting that HR2 peptides, identified against SARS-CoV, may also inhibit SARS-CoV-2 (Xia et al., 2020b) . HR2 based inhibitory peptides acting on SARS-CoV and MERS-CoV were reviewed by Tang et al. (Tang et al., 2020) , creating possibilities for peptide or small molecule based anti-CoV fusogenics, which can arrest membrane fusion in SARS-CoV-2. Recently, a few HR2 sequence-based fusion inhibitors have been reported to potentially inhibit cell fusion in a dual-split protein (DSP) based cell fusion assay on SARS-CoV-2 (Cannalire et al., 2020) . Xia et al. developed a pan-coronavirus inhibitor EK1 that targets the HR1 domain and inhibits coronavirus infection (Xia et al., 2019) . They also generated a highly potent lipopeptide EK1C4, which acts as a pan-coronavirus fusion inhibitor, targeting the spike protein (Xia et al., 2020a) . EK1C4 was developed by adding cholesterol residue to the EK1 peptide to improve the inhibitory activity against SARS-CoV-2 (Mahendran et al., 2020) . EKIC4 was found to have remarkable inhibitory activity against membrane fusion mediated by SARS-CoV-2 spike protein and also against entry of pseudotyped human coronaviruses including SARS-CoV and MERS-CoV. EK1C4 potently inhibits SARS-CoV-2 replication, with an EC50 value of 36.5 nM, which is more potent than the EK1 peptide with an EC50 value of 2.47 µM (Cannalire et al., 2020) . Another HR2 sequence-based J o u r n a l P r e -p r o o f lipopeptide fusion inhibitor, termed IPB02, showed highly potent activities in inhibiting SARS-CoV-2 spike protein-mediated cell-cell fusion and pseudovirus transduction .

EK1C4 has many advantages over other peptide drugs, as it can be inhaled as an aerosol formulation, reducing the viral load in the lung, and alleviating the pulmonary inflammatory reaction . The intranasal application of EK1C4 indicates that it could be used as an effective therapeutic against infection by SARS-CoV-2 (Xia et al., 2020a) . The sequence of its target, the HR1 domain in the S2 subunit of the S protein, is highly conserved, which means EK1C4 cannot easily induce drugresistant mutations. 

The coronavirus alters the host transcription machinery in its favor to synthesize its proteins once the virus enters the host cell. The SARS-CoV positive stranded RNA genome encodes two open reading frames (ORF), ORF1a and ORF1b, which on translation produces two polyproteins (pp), pp1a and pp1ab. These polyproteins are proteolytically cleaved to generate 16 non-structural proteins, required for viral replication (Snijder et al., 2016) , which include two proteases, 3-chymotrypsin-like protease (3CL pro / Nsp5) and papain-like protease (PL pro / Nsp3) that mediate the proteolytic processing of the polyprotein. The 3CL pro of SARS-CoV-2 has a 99.02% sequence identity with the SARS-CoV (Tahir ul Qamar et al., 2020). As the active sites of 3CL pro are highly conserved in multiple coronaviruses , the possibility of designing peptide inhibitors targeting the substrate binding pocket of SARS-CoV-2 3CL pro has been explored and two peptidomimetic aldehydes 11a and 11b were identified. Both exhibited excellent inhibitory activity and potent anti-SARS-CoV-2 infection activity (Fig. 2) . The another protease, PLPro (Papain like protease) involved in the proteolytic processing of the replicase polyprotein, which also plays a significant role in antagonizing the host's innate immunity, is an attractive antiviral drug target as well (Lei et al., 2018) . Target based virtual ligand screening against the ZINC drug database identified Glutathione, currently used for the treatment of liver diseases (Sacco et al., 2016) , as effective against PLPro with a docking score of 20. 

Coronavirus genome replication and transcription involve coordinated processes of both continuous and discontinuous RNA synthesis mediated by the viral replicase, a huge protein complex encoded by the 20-kb replicase gene (Sola et al., 2015) . The replicase-transcriptase proteins, together with other viral proteins and possibly cellular proteins, assemble into membrane-bound replication-transcription complexes (RTC). The central component of coronoviral replication/transcription is Nsp12 (RNA dependent RNA polymerase/RdRp) (te Velthuis et al., 2010) , which is the primary target for remdesivir, a nucleoside analog antiviral inhibitor, currently used for SARS-CoV-2 Shannon et al., 2020) . Remdesivir exhibits a broad spectrum of anti-viral activity against many viruses, including Ebola, Nipah and the respiratory syncytial virus (RSV), SARS-CoV and MERS-CoV (Saha et al., 2020) . This molecule is assumed to affect the viral RNA synthesis by a delayed chain termination process in the three coronaviruses (MERS-CoV, SARS-CoV and SARS-CoV-2). Remdesivir is currently being tested in the clinic in many countries and approved for emergency treatment of patients with COVID-19 (Hillen et al., 2020) . A recent study indicated that remdesivir was effective in lowering the respiratory tract infection of COVID-19 adult patients in a double blind, randomized placebo controlled trial (Beigel et al., 2020) . The synthesis of viral RNA by Nsp12 possibly occurs with the assistance of Nsp7 and Nsp8 as cofactors (Shannon et al., 2020) . Nsp8 synthesizes a primer of 6 nucleotide lengths for RdRp RNA synthesis, and the Nsp7-Nsp8 complex increases the binding of Nsp12 to RNA and enhances the RdRp enzymatic activity of Nsp12. The interactions of these non-structural proteins also offers great therapeutic possibilities, specifically investigating the Nsp12-Nsp8 interaction (Mutlu et al., 2020) .

Nsp9, highly conserved in beta coronaviruses, is assumed to mediate viral replication, overall virulence, and viral genomic RNA reproduction. Selinexor, a synthetic peptide, an inhibitor of CRM1 (Chromosome region maintenance protein), also known as exportin 1 (XPO1) involved in nuclear export, could be effective in inhibiting the interactions between Nsp9 and nuclear pore proteins (Gordon et al., 2020; Wang and Liu, 2019) . Low oral doses of this peptide is being tested in ongoing clinical trials against COVID-19 (Uddin et al., 2020) . Ternatin 4-N-methylated cyclic hexapeptide, derived from mushrooms, inhibits adipogenesis at low concentrations (EC50 = 20 nm) (Ito et al., 2009) and becomes cytotoxic at a 10-fold higher concentration (Shimokawa et al., 2008) and known to kill J o u r n a l P r e -p r o o f cancer cells (Carelli et al., 2015) , also inhibits the translation machinery. Since ternatin 4 can affect the host translation process, it is included as a preclinical compound that could be repurposed against SARS-CoV-2.

Epigenetic changes that regulate chromatin rearrangement have been implicated in the pathophysiology of viral infection (Chlamydas et al., 2021) . Several studies have highlighted the importance of epigenetic regulators in SARS-CoV studies (Clarke et al., 2014; Schäfer and Baric, 2017) . Recently, DNA methylation analysis of ACE2 expression has been shown to throw light on the epidemiology of SARS-CoV-2 infection (Corley, M.J.; Ndhlovu, 2020) . ACE2 expression is also found to be regulated by Bromodomain and extraterminal (BET) proteins which are epigenetic readers (Qiao et al., 2020) .

Gordon etal has identified an interaction of BRD4 with the E protein of SARS-CoV-2, which highlights possibilities of exploring peptide based bromodomain inhibitors as SARS-CoV-2 therapeutics. In the same SARS-CoV-2 interactome study, HDAC2 was found to have a high confidence interaction with the viral protein Nsp5 (Gordon et al., 2020) . Nsp5 is thought to inhibit HDAC2 transport into the nucleus, thereby enhancing inflammation and interferon response. We suggest looking for peptide inhibitors of Nsp5, which seems to be the switch to start inflammation in COVID-19. Also, HDAC inhibitors have been proposed to serve as preventive drug against COVID-19 (Takahashi et al., 2021) .

These suggest epigenetic interventions such as epidrugs could serve as promising therapeutic or prophylactic options (Pruimboom, 2020) . The approach used for the discovery of Apicidin, a natural tetrapeptide inhibitor of HDAC via a cyclic α3β-tetrapeptide scaffold (Olsen and Ghadiri, 2009 ) is interesting and can be used to identify more anti-coronaviral peptide inhibitors.

Besides RNA-dependent RNA polymerase, RNA helicase and protease activities, common to RNA viruses, the coronavirus replicase also employs a variety of RNA processing enzymes that are not (or extremely rarely) found in other RNA viruses (Mousavizadeh and Ghasemi, 2020) . Several enzymatic activities are required for the formation of a cap structure in the viral RNA, followed by Ribose 2′-Omethylation of the cap that provides a mechanism for viruses to escape host immune recognition (Daffis et al., 2010) . RNA capping in CoVs involves the activities of several nonstructural proteins (Wang et al., 2015) .

The RTC uses the genome to synthesize progeny genomes and a series of subgenomic mRNAs, using negative-stranded intermediates. The structural proteins S, M, E and N are generated by the translation of these mRNAs, which participate in the formation of mature virions. The E (envelope) protein of SARS-CoV-2 plays key roles in various phases of the viral life cycle, such as envelope formation, pathogenesis, budding and assembly. Unlike the other major structural proteins, N is the only protein that functions primarily to bind to the CoV RNA genome, constituting the nucleocapsid to make new virons (de Haan and Rottier, 2005) . The N protein of SARS-CoV-2 is highly homologous to that of SARS-CoV (Kang et al., 2020) . A recent study by Cascarina et al. reports that the N protein of SARS-CoV-2 is capable of regulating the biomolecular interaction with RNA and key host cell proteins (Cascarina and Ross, 2020) . The N protein also binds to the stress granule proteins, which induce the host's immune response (Onomoto et al., 2014) . The manipulation of stress granules could be promising in inhibiting the replication of coronaviruses (Miller, 2011; Nakagawa et al., 2018) . N protein is also shown to interact with the Ras-GTPase activating SH3-domain-binding-protein 1 (G3BP1) (Gordon et al., 2020) , which inhibits RNA virus replication .

After the virus gains access to the target cell, the host immune system recognizes the whole virus or its surface epitopes, and elicits an innate or adaptive immune response. The SARS-CoV-2 virus infects through the naso-oral route, followed by infection in cells expressing the ACE2 receptor in the lung.

These viruses dampen the anti-viral IFN responses by evading the innate immune cells, resulting in unrestrained virus replication. At the same time, the activation of macrophages and other immune cells, cause the production of cytokines.

When SARS-CoV-2 infects the upper and lower respiratory tract, it can cause a mild or highly acute respiratory syndrome with consequent release of pro-inflammatory cytokines, such as the interleukins (Conti et al., 2020) . A case report shows that the compstatin-based complement C3 peptidic inhibitor AMY-101 was successful in treating a patient with severe ARDS due to COVID-19 pneumonia (Mastaglio et al., 2020) . Anakinra, an interleukin-1 receptor antagonist, currently used for the treatment of rheumatoid arthritis (Mertens and Singh, 2009) , is beneficial in association with remdesivir in controlling the pathological immune response to SARS-CoV-2 (Franzetti et al., 2020). . In a murine model of SARS-CoV infection, increased production of chemokines was correlated with increased migration of NK cells into the lungs (Chen et al., 2010) . The high expression of chemokines in the lungs of COVID-19 patients also seem to facilitate NK cell migration from the peripheral blood to the lungs (Ahmed et al., 2020) .A transcriptomic signature analysis also revealed an infiltration of the NK cells into lungs (Liao et al., 2020) , possibly mediated by the CXCR3 pathway (Zang et al., 2019) . Since chemokines are vital in attracting NK cells to clear the virus, peptide inhibitors blocking such chemokine receptors are promising drugs for SARS-CoV-2. Moreover, peptide antagonism is an established mechanism for NK cell activation, and there is a major scope for more peptide therapeutics in this aspect (Fadda et al., 2010) .

Adaptive immune response and immunological memory are crucial for the success of a vaccine. An effective vaccine should induce a specific immune response against the specific antigen by selectively (Kiyotani et al., 2020) . Immunoinformatic tools were used to analyse the proteome of SARS-CoV-2 and an epitope with HLA allele binding affinity, ITLCFTLKR has been identified as a vaccine candidate (Joshi et al., 2020) (Fig. 3) . Similarly, peptides binding to the MHC class I and MHC class II were promising epitope based peptide vaccine candidates, when envelope protein was used as an immunogenic target (Abdelmageed et al., 2020) . A total of 10 epitopes based on the structural proteins designed by molecular docking analysis against MHC-I were identified which have the potential to be developed as peptide vaccine against SARS-CoV-2 (Waqas et al., 2020) . A computational analysis identified the sequence KRSFIEDLLFNKV as particularly conserved in many coronaviruses, ranging from the common cold coronavirus to SARS-CoV-2. This sequence motif can J o u r n a l P r e -p r o o f form the basis for proposing a specific synthetic vaccine epitope and peptidomimetic agent (Robson, 2020) .

Epitopes are immunogenic components, which can also be used in vaccine discovery studies (Palatnikde-Sousa et al., 2018) . Since discovering epitopes by traditional experimental methods is often expensive and time-consuming, in silico approaches become the preferred strategy. Thus, it can be rightly said that computational immunoinformatics is the basis of epitope vaccine development (Parvizpour et al., 2020) . Many epitope studies have been conducted with SARS-CoV proteins (Lin et al., 2003; Wang et al., 2016) . The Immune Epitope Database and Analysis Resource (IEDB) that catalogs available data related to other coronaviruses, can be used effectively to predict and identify candidate targets for immune responses to SARS-CoV-2 (Grifoni et al., 2020) . A study carried out by comparing the SARS-CoV-2 and the human proteomes identified certain epitopes embedded in the S protein that could serve as possible vaccine candidates (Lucchese, 2020) . In another study, two immunodominant linear B-cell epitopes on the S glycoprotein of SARS-CoV-2 that could elicit neutralizing antibodies, have been identified (Poh et al., 2020) . Nucleocapsid proteins within SARS-CoV-2 contain multiple Class I epitopes with predicted HLA restrictions, consistent with a broad population coverage, which can be used to develop a CTL peptide vaccine against COVID-19 (Herst et al., 2020) . A multiepitope vaccine construct to combat SARS-CoV-2 infection was made from spike S protein and orf1ab polyprotein against B and T lymphocytes (Almofti et al., 2021) . Recently, a comprehensive reverse-vaccinology workflow that can be used to identify and shortlist potential T-and B-cell epitopes has also been proposed (Hisham et al., 2021) . 

Various disciplines, such as genomics and proteomics, have a major role in combating COVID-19 (Rana et al., 2020) . It is important to note that intensive research with the SARS-CoV-2 virus is ongoing to understand its pathogenesis and mechanism of virulence. Genomics is employed in identifying genomic variants of SARS-CoV-2, which is highly important, especially when the penetrance of host genetic variants is high (Geller et al., 2020) . The information related to the genetic variants of SARS-CoV-2 is a decision making tool, in terms of patient care, prioritization for therapies, clinical research, and public health containment practices. In addition, genomics studies are significant in delineating the host factors associated with the variability in susceptibility, infectivity, and also the severity of the disease (Geller et al., 2020; Kellam and Weiss, 2006) . The progress of these Omics studies can be extrapolated to applications in many fields, including immunology. This supports a J o u r n a l P r e -p r o o f deeper level of knowledge and the provision of substantial data used in computational studies, namely immunoinformatics (Tilocca et al., 2020) .

Proteomics facilitates the deciphering of the knowledge related to structure-function relationships of protein targets. This information would provide novel insights into drug development to prevent infection and as well as to control transmission (Thakur, 2020) . Several molecular docking, dynamics and pharmacology approaches have been investigated based on the binding affinity of drug components against COVID-19 (Daoud et al., 2021; Noureddine et al., 2021; Vincent et al., 2020) . Proteomics based directed drug repurposing might be a rapid response solution for the COVID-19 pandemic, based on the experience with SARS-CoV, MERS-CoV, or other coronaviruses. Although many countries are vaccinating their citizens, there is no effective drug to treat COVID-19. We urge the research community to exploit the omics approaches to rapidly identify new potential drug molecules.

The development of peptide therapeutics is considered risky, due to the poor performance in ADME (absorption, distribution, metabolism, elimination) properties. However, pharmaceutical companies are considering this strategy due to its many advantages. The data presented in this review reinforces the need for further studies and new therapeutic proposals to combat the threat of COVID-19. The knowledge achieved in the treatment of SARS-CoV may be used to enhance this process. It should be noted that the accuracy and coverage of this review will be short-lived, due to the rapid advances being made in this area; however, this review will be significant in accelerating the development of novel solutions for COVID-19.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

The author declares no conflict of interest. All authors have approved the final version of the manuscript. (Liu et al., 2009) J o u r n a l P r e -p r o o f (Akaji et al., 2008) J o u r n a l P r e -p r o o f

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Nsp3 of coronaviruses: Structures and functions of a large multi-domain protein

Therapeutic options for the 2019 novel coronavirus (2019-nCoV)

Virucidal activity of a scorpion venom peptide variant mucroporin-M1 against measles, SARS-CoV and influenza H5N1 viruses

The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing

Identification of an epitope of SARS-coronavirus nucleocapsid protein

Identification of a minimal peptide derived from heptad repeat (HR) 2 of spike protein of SARS-CoV and combination of HR1-derived peptides as fusion inhibitors

Novel immunodominant peptide presentation strategy: a featured HLA-A*2402-restricted cytotoxic T-lymphocyte epitope stabilized by intrachain hydrogen bonds from severe acute respiratory syndrome coronavirus nucleocapsid protein

Synthetic peptides derived from SARS coronavirus S protein with diagnostic and therapeutic potential

Epitopes for a 2019-nCoV vaccine

En route to Peptide Therapeutics for COVID 19: Harnessing Potential Antigenic Mimicry Between Viral and Human Proteins

The Potential of Antiviral Peptides as COVID-19 Therapeutics

The novel Coronavirus (SARS-CoV-2)

The first case of COVID-19 treated with the complement C3 inhibitor AMY-101

Anakinra for rheumatoid arthritis

Stress Granules and Virus Replication

The Signaling Pathways, and Therapeutic Targets of Antiviral Agents: Focusing on the Antiviral Approaches and Clinical Perspectives of Anthocyanins in the Management of Viral Diseases

Learning from the Past: Possible Urgent Prevention and Treatment Options for Severe Acute Respiratory Infections Caused by 2019-nCoV

Antimicrobial peptides and other peptidelike therapeutics as promising candidates to combat SARS-CoV-2

Genotype and phenotype of COVID-19: Their roles in pathogenesis

Current treatment options and the role of peptides as potential therapeutic components for Middle East Respiratory Syndrome (MERS): A review

Targeting SARS-CoV-2 Nsp12/Nsp8 interaction interface with approved and investigational drugs: an in silico structure-based approach

Inhibition of Stress Granule Formation by Middle East Respiratory Syndrome Coronavirus 4a Accessory Protein Facilitates Viral Translation, Leading to Efficient Virus Replication

A Review on SARS-CoV-2 Virology

DFT and molecular docking study of chloroquine derivatives as antiviral to coronavirus COVID-19

Discovery of potent and selective histone deacetylase inhibitors via focused combinatorial libraries of cyclic alpha3beta-tetrapeptides

Antiviral innate immunity and stress granule responses

Editorial: Epitope Discovery and Synthetic Vaccine Design

COVID-19: Current understanding of its Pathophysiology, Clinical presentation and Treatment

Epitope-based vaccine design: a comprehensive overview of bioinformatics approaches

Two linear epitopes on the SARS-CoV-2 spike protein that elicit neutralising antibodies in COVID-19 patients

The receptor-binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients

Methylation Pathways and SARS-CoV-2 Lung Infiltration and Cell Membrane-Virus Fusion Are Both Subject to

Targeting transcriptional regulation of SARS-CoV-2 entry factors ACE2 and TMPRSS2

A comprehensive overview of proteomics approach for COVID 19: new perspectives in target therapy strategies

Preliminary bioinformatics studies on the design of a synthetic vaccine and a preventative peptidomimetic antagonist against the SARS-CoV-2 (2019-nCoV, COVID-19) coronavirus

Glutathione in the treatment of liver diseases: insights from clinical practice

Molecular Mechanism of Remdesivir for the Treatment of COVID-19: Need to Know More

Inhibition of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) infectivity by peptides analogous to the viral spike protein

SARS: Challenge of the New Century

Epigenetic Landscape during Coronavirus Infection. Pathog

Remdesivir and SARS-CoV-2: Structural requirements at both nsp12 RdRp and nsp14 Exonuclease active-sites

Biological Activity, Structural Features, and Synthetic Studies of (−)-Ternatin, a Potent Fat-Accumulation Inhibitor of 3T3-L1 Adipocytes

Features of protein-protein interactions that translate into potent inhibitors: topology, surface area and affinity

The Nonstructural Proteins Directing Coronavirus RNA Synthesis and Processing

Continuous and Discontinuous RNA Synthesis in Coronaviruses

A hexapeptide of the receptorbinding domain of SARS corona virus spike protein blocks viral entry into host cells via the human receptor ACE2

Structural basis of SARS-CoV-2 3CLpro and anti-COVID-19 drug discovery from medicinal plants

Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine

Histone deacetylase inhibitors suppress ACE2 and ABO simultaneously, suggesting a preventive potential against COVID-19

Coronavirus membrane fusion mechanism offers a potential target for antiviral development

The RNA polymerase activity of SARS-coronavirus nsp12 is primer dependent

Proteomics and Its Application in Pandemic Diseases

Computational Immune Proteomics Approach to Target COVID-19

New Pathways of Mutational Change in SARS-CoV-2 Proteomes Involve Regions of Intrinsic Disorder Important for Virus Replication and Release

Exportin 1 inhibition as antiviral therapy

Antiviral peptides as promising therapeutic drugs

Molecular Docking Studies on the Antiviral Effects of Compounds From Kabasura Kudineer on SARS-CoV-2 3CLpro

Structural basis of RNA cap modification by SARS-CoV-2

The past, present, and future of CRM1/XPO1 inhibitors

Immunodominant SARS Coronavirus Epitopes in Humans Elicited both Enhancing and Neutralizing Effects on Infection in Non-human Primates

Broad-Spectrum Coronavirus Fusion Inhibitors to Combat COVID-19 and Other Emerging Coronavirus Diseases

Coronavirus nsp10/nsp16 Methyltransferase Can Be Targeted by nsp10-Derived Peptide In Vitro and In Vivo To Reduce Replication and Pathogenesis

Determine the Potential Epitope

Based Peptide Vaccine Against Novel SARS-CoV-2 Targeting Structural Proteins Using Immunoinformatics Approaches

Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion

A pan-coronavirus fusion inhibitor targeting the HR1 domain of human coronavirus spike

Fusion mechanism of 2019-nCoV and fusion inhibitors targeting HR1 domain in spike protein

Characterization of the heptad repeat regions, HR1 and HR2, and design of a fusion core structure model of the spike protein from severe acute respiratory syndrome (SARS) coronavirus

Design of wide-spectrum inhibitors targeting coronavirus main proteases

G3BP1 inhibits RNA virus replication by positively regulating RIG-I-mediated cellular antiviral response

Suppression of SARS-CoV entry by peptides corresponding to heptad regions on spike glycoprotein

Senescent hepatocytes enhance natural killer cell activity via the CXCL-10/CXCR3 axis

The first-in-class peptide binder to the SARS-CoV-2 spike protein

Functional exhaustion of antiviral lymphocytes in COVID-19 patients

Screening and identification of severe acute respiratory syndromeassociated coronavirus-specific CTL epitopes

Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2

A Novel Coronavirus from Patients with Pneumonia in China

Design of Potent Membrane Fusion Inhibitors against SARS-CoV-2, an Emerging Coronavirus with High Fusogenic Activity

Coronaviruses -drug discovery and therapeutic options

The authors gratefully acknowledge the contribution from Ms. Malavika Saji for creating illustrations.Special thanks to Dr. Susanna Wright for language revising and editing the manuscript.