key: cord-0976589-noi3kkb7
authors: Heydari, Hamid; Golmohammadi, Reza; Mirnejad, Reza; Tebyanian, Hamid; Fasihi-Ramandi, Mahdi; Moosazadeh-moghadam, Mehrdad
title: Antiviral peptides against Coronaviridae family: A review
date: 2021-03-04
journal: Peptides
DOI: 10.1016/j.peptides.2021.170526
sha: 1edb4e86e4b0a7c09a7ea387e042ef06166e0860
doc_id: 976589
cord_uid: noi3kkb7

The Coronaviridae family comprises large enveloped single-stranded RNA viruses. The known human-infecting coronaviruses; severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), novel SARS-CoV-2, human coronavirus (HCoV)-NL63, HCoV-229E, HCoV-OC43 and HKU1 cause mild to severe respiratory infections. The viral diseases induced by mammalian and avian viruses from Coronaviridae family pose significant economic and public health burdens. Due to increasing reports of viral resistance, co-infections and the emergence of viral epidemics such as COVID-19, available antiviral drugs show low or no efficacy, and the production of new treatments or vaccines are also challenging. Therefore, demand for the development of novel antivirals has considerably increased. In recent years, antiviral peptides have generated increasing interest as they are from natural and computational sources, are highly specific and effective, and possess the broad-spectrum activity with minimum side effects. Here, we have made an effort to compile and review the antiviral peptides with activity against Coronaviridae family viruses. They were divided into different categories according to their action mechanisms, including binding/attachment inhibitors, fusion and entry inhibitors, viral enzyme inhibitors, replication inhibitors and the peptides with direct and indirect effects on the viruses. Reported studies suggest optimism with regard to the design and production of therapeutically promising antiviral drugs. This review aims to summarize data relating to antiviral peptides particularly with respect to their applicability for development as novel treatments.

The Coronaviridae family comprises large enveloped single-stranded RNA viruses with genomes ranging from 25 to 32 kb. The International Committee on Taxonomy of Viruses (ICTV) divided this family into Orthocoronavirinae and Letovirinae sub-families and according to phylogenetic relationships Orthocoronavirinae consists of four genera including Alphacoronavirus, Betacoronavirus, Gammacoronavirus and Deltacoronavirus [1, 2] . The alphacoronaviruses and betacoronaviruses infect mammals and usually cause respiratory disease in humans and gastroenteritis in animals. The gammacoronaviruses and deltacoronaviruses infect avian species; however, some of them have also been found in mammalian hosts [3, 4] .

The known human-infecting coronaviruses, severe acute respiratory syndrome coronavirus [2, 5, 10] . However, these approaches are not effective against a broad range of viral infections. Moreover, due to increasing reports of viral resistances, co-infections, and the emergence of viral epidemics such as COVID-19, available antiviral drugs show low or no efficacy against several coronavirus infections and the production of new vaccines is also challenging and time consuming [11] . Therefore, demand for the development of novel antivirals has considerably increased that may serve as supplementary or alternative to the currently used drugs. Employing antimicrobial peptides is an alternative option to circumvent the issues mentioned earlier. The features that suggest them as potent candidates for pharmacological applications are their remarkable structural and functional diversity. The wide range of biological activities of antimicrobial peptides proposes that they could be incorporated in the treatment strategies against bacterial, viral, and fungal infections [12] [13] [14] [15] . Antiviral peptides have generated an increasing interest as a promising therapeutic in recent years. They have been obtained from natural, biological, and computational sources and are highly specific and effective in low concentrations and possess broad-spectrum activities with minimum side effects and host toxicity [16, 17] .

Here, we have made an effort to compile and review the antiviral peptides with activity against the viruses of Coronaviridae family and their mechanisms of action, which may help the researchers to design and produce novel antiviral drugs.

Antiviral peptides affect viruses by inhibiting the essential stages of their life cycle or components such as inhibition of attachment, fusion, host cell entry, intracellular viral replication and transcription, maturation, and viral enzymes. Direct interaction with virus particles and its effect on viral pathogenesis has also been reported by some antiviral peptides [17] [18] [19] .

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

The interaction of attachment proteins expressed on the virion surface with the host cell receptors is a vital initial step in the viral infections [20] . The viral genome of coronaviruses encodes spike (S), envelope (E), membrane (M), and nucleocapsid (N) structural proteins. The S protein has extracellular, transmembrane and intracellular domains, and also, the extracellular domain is divided into two subunits: S1 and S2. The S1 subunit includes the receptor-binding domain (RBD).

The RBD comprises the N-terminal domain (NTD) and the C-terminal domain (CTD). SARS-CoV and SARS-CoV-2 bind to the angiotensin-converting enzyme 2 (ACE2) (abundant on the lung and small intestine cells surfaces), and MERS-CoV binds to proteinaceous dipeptidyl peptidase 4 (DPP4) (expressed on the lung and kidney cells surfaces) by CTD [21, 22] . The S protein is an attractive target for the development of antiviral agents against CoVs.

In a study conducted by Zheng et al., anti-SARS-CoV activity of two peptides (P2 and P6) was demonstrated using a cytopathic effect (CPE)-based assay. These peptides were designed and synthesized based on the variations of the S1 domain. They effectively protected cells from the CPEs and reduced viral titer compared to the untreated controls. Significant synergistic antiviral effects were also detected in the combination of two peptides. They suggested that P2 was not a competitive peptide for the ACE2 receptor binding but may hamper conformation changes of the binding site, and P6 binds to the S protein and interferes with the virus-cell interactions [23] ( Figure 1A ). In the other research, ACE2-derived peptides (peptides representing critical regions of ACE2) could block ACE2-S protein interaction and inhibit virus binding to the host cell. The evaluated peptides (P4, P5 and P6) exhibited a notable antiviral activity with the relative low 50% inhibitory concentrations (IC50) [24] . The attachment blocker small peptides (SP-4, SP-8 and SP-J o u r n a l P r e -p r o o f 10) were also synthesized in a previous study based on S protein's receptor-binding regions (Molecular weight ~ 1.3-1.4 KDa). Their efficient inhibitory activity against S protein binding to the ACE2 was detected using the enzyme-linked immunosorbent assay (ELISA) method in Vero E6 cells [25] .

Moreover, Chang et al. indicated that two synthetic peptides, GA91 and GA101 (corresponding to SARS-CoV Spike protein) block the binding of the SARS-CoV S protein to the host cells, using Vero E6 cells in adhesion assay [26] . In a different study, a hexapeptide, which was derived from RBD of the S protein, showed antiviral activity against SARS-CoV and HCoV-NL63. This peptide blocks the binding sites essential for the initial viral attachment to the respective receptor ( Figure   1A ) and effectually inhibits CoVs replication in cell culture [27] .

In the recent in-silico studies, the inhibitor peptides targeting the interaction between SARS-CoV-2 spike protein and ACE2 were designed using computational approaches [28, 29] . Baig and colleagues have presented an ACE2-based peptide (18 aa peptide) that could block the viral attachment [28] . Furthermore, the S protein of SARS-CoV-2 was targeted by an inhibitor protein (ΔABP-D25Y) in Jaiswal et al., study. This protein includes two α-helical peptides which homologues to the ACE2 and also, its attachment to S protein is competitive [29] ( Figure 1B ).

Recent investigations showed that there are several potential heparin-binding sites located within the S1 domain of SARS-CoV-2. Heparin-binding peptides (HBPs) are capable of stopping SARS-CoV-2 infection. The interaction between HBPs and the S1 protein of SARS-CoV-2 was also described [30] . Another antimicrobial peptide with anti-SARS-CoV-2 activity is human defensin 5 (HD5). This alpha-defensin is secreted by intestinal Paneth cells and by neutrophils. It has high affinity to ACE2 and dramatically protects host cells from the adherence of the virus. HD5 is also capable of attaching SARS-CoV-2 S1 protein and affects its efficiency [31, 32] .

The characteristics of the antiviral peptides with binding inhibitory activity against humaninfecting coronaviruses are expressed in Table 1 .

As mentioned above, the extracellular domain of S protein contains two subunits; S1 and S2. The Following endocytosis, the activated cysteine protease cathepsin L can cleave the S2' site in acidic conditions and trigger the subsequent fusion steps and CoVs genome releasing [21, 22] .

In a study conducted by Liu et al., the anti-SARS-CoV activity of the synthesized peptides based on HR1 and HR2 regions of S protein was investigated. One peptide derived from HR2 (CP-1) had inhibitory activity against SARS-CoV by binding to the HR1 and interfering with the conformational rearrangement (six-helix bundle formation) viral fusion. A HR1-derived peptide (NP-1) showed a marginal antiviral activity [33] . The inhibitory activity against membrane fusion and viral entry has also been described by a peptide derived from the SARS-CoV S2 protein HR J o u r n a l P r e -p r o o f segments in another research [34] . Moreover, Zheng and colleagues synthesized the peptides based on the sequence of SARS-CoV S2 domain. Significant antiviral effects were observed for two peptides (P8 and P10) through binding to the S2 protein and preventing virion-cell membrane fusion. They significantly protected cells from CPEs and reduced viral titer in the culture media.

The peptide P8 had the highest antiviral potency and no virus was detected after P8 treatment.

Furthermore, peptide combinations significantly improved their antiviral effects [23] . In the Sainz Jr et al., study, the peptides' ability analogous to the S2 subunit to inhibit SARS-CoV plaque formation has also been described [35] . Anti-SARS-CoV properties of HR-based antiviral peptides have been reported in more researches [36] [37] [38] . Figure [40] . The inhibitory model of such peptides against coronaviruses is shown in Figure   3 .

Several researches have also been performed regarding antiviral activity of HR regions-based peptides against MERS-CoV. In the Lu et al., study, a MESR-CoV HR2 analogous peptide (HR2P) was synthesized and its antiviral activity was investigated against this virus. The peptide could inhibit MERS-CoV fusion through interaction with the viral HR1 domain and heterologous sixhelix bundle formation [41] . A similar result was presented in the study by Channappanavar et al. [42] . A fusion inhibitor named MERS-five-helix bundle (MERS-5HB) was synthetized by Sun et al. MERS-5HB was derived from the MERS six-helix bundle and consisted of three copies of HR1 and two copies of HR2. Lack of one HR2 in 5HB led to its interaction with a native HR2 of the MERS-CoV and the fusion step interruption [43] . As mentioned above, six-helix bundle (hexameric structure) formation by HR1 and HR2 is necessary for viral fusion and entry. Wang et al., have designed the hydrocarbon-stapled peptide and lipopeptide with a hydrocarbon tail in the two separate studies that could effectively block MERS-CoV formation hexameric structure [44, 45] . The MERS-CoV fusion inhibitory peptides derived from HR2 domain of HKU4 (bat coronavirus) have also been reported. The HKU4-HR2Ps binds to HR1 of MERS-CoV with high stability and blocks the fusion process [46] (Figure 2 ). Recently, a gold nanorod-based HR1 peptide (PIH-AuNRs) was proposed as MERS-CoV fusion inhibitor. The HR1 peptide inhibitor (PIH) derived from viral HR2 region was conjugated by potential biocompatible and site-specific carriers (AuNRs). This complex could completely inhibit MERS-CoV fusion [47] .

In an in-silico study conducted by Ling et al., an antiviral peptide targeting SARS-CoV-2 fusion was described. They predicted the HR1 and HR2 regions in S protein of SARS-CoV-2 using sequence alignment and simulated forming of the fusion core. Then, they designed HR2-baseed peptide that can competitively bind with HR1 to inhibit viral fusion core forming [48] . Table 2 .

The coronavirus enzymes' pivotal roles, including proteases, helicases, RNA-dependent RNA polymerase (RdRp), and methyltransferase, have been well characterized in the viral life cycle.

Coronaviruses genome contains at least 6 open reading frames (ORFs). The ORF1ab encodes the overlapping polyproteins which are cleaved into non-structural proteins (nsps) by the main protease (M pro or 3CL pro ) and the papain-like protease (PL pro ) [57] . Due to these cysteine proteases' critical role in viral gene expression and replication, they are favorable targets for the antiviral drug design.

In the study conducted by Gan et al., the designed octapeptide inhibited the SARS-CoV M pro and blocked replication of the virus [58] . Similarly, the synthetized dipeptides (6a and EP128533) and tetrapeptide inhibited several CoVs by inhibiting their M pro [59] [60] [61] . In the previous studies, SARS-CoV M pro inhibitory activities of the peptide-based compounds (tetrapeptide, pentapeptides and octapeptides) were also proposed without biological experiments [62] [63] [64] . A recent study indicated that, in-silico hydrolysis of marine fish proteins, gastrointestinal enzymes generated active peptides. Some of them were identified as high-affinity oligopeptides binder to the M pro of SARS-CoV-2. According to their results, the identified oligopeptides could be used as potential SARS-CoV-2 inhibitor drugs [65] .

In addition, blocking other enzyme of SARS-CoV (Methyltransferase) was demonstrated previously by the synthesized peptides. The nsp16 acts as a methyltransferase and plays an J o u r n a l P r e -p r o o f essential role in the life cycle of coronaviruses. The designed peptides could markedly inhibit the activity of methyltransferase and thus viral replication [66] . Table 3 shows the characteristics of antiviral peptides with potential inhibitory activity against coronaviruses enzymes.

In the study performed by Lo et al., a synthesized peptide could inhibit replication of HCoV-229E in the host cells, significantly through the interference of the oligomerization of the viral nucleocapsid protein [67] . The application of such a strategy may assist the design and development of antiviral drugs against other human-infecting coronaviruses. Table 4 shows the characteristics of the viral replication inhibitor peptides.

The virucidal activity of a confirmed antimicrobial peptide against SARS-CoV was reported in the Li et al., study. The infectivity of virus decreased significantly via direct interaction of the peptide (mucroporin-M1) with the virus envelope [68] . The characteristics of mucroporin-M1 are shown in Table 5 .

Indirect effects of human beta-defensin 2 (HBD 2) (an antimicrobial peptide produced by epithelial cells) against MERS-CoV were reported in the previous studies. HBD 2 enhanced primary antiviral innate immunity and effective adaptive immune responses [69, 70] . Human cathelicidin (LL-37) also reduces the pathology of COVID-19 by affecting regulatory T cells. The probable role of LL-37 in the down-regulation of interleukin-17, which is involved in thrombosis and acute respiratory distress syndrome, was reported recently [71] . study showed three chemically synthesized peptides (F, H and S) that had sequence homologies (same motifs identified in the S protein of TGEV) were able to inhibit TGEV infection through competition with binding the pAPN [72] . Similarly, an antiviral peptide's potential inhibitory effect was observed using a phage bearing the peptide with affinity to pAPN [73] . Furthermore, the inhibitory activity of a membrane (M) protein-derived peptide was demonstrated in the other study. Peptide TGEV-M7 was able to significantly reduce the virus's ability to infect host cells [74] .

Cao et al., indicated the antiviral activity of two peptides (L and W) against porcine epidemic diarrhea virus (PEDV). The PEDV is another swine pathogen that causes severe diarrhea and dehydration. These peptides share a consensus motif with S1 protein of PEDV and inhibit the binding of the virus to the host cells [75] .

FIPV is a type of feline coronavirus (FCoV) and belongs to the alphacoronaviruses. It can cause lethal disease in cats due to multiple organs involvement. The S1 domain of FIPV S protein also contains the RBD. Doki et al., synthesized peptides based on the S1 domain sequence and investigated their inhibitory effects. Two peptides (I-S1-9 and I-S1-16) inhibited the binding and infectivity of FIPV significantly. Moreover, significant reduction of viral adsorption to cells was observed using peptide I-S1-9 [76] .

IBV that belongs to gammacoronavirus, is the etiologic agent of complex and highly contagious respiratory disease in chickens which remains an economic problem. Bo et al., showed that a phage-displayed peptide blocks binding the IBV S protein and inhibits virus infectivity and CPE occurrence in HeLa cells [77] . The other studies indicated that swine intestine antimicrobial peptide (SIAMP) inhibits IBV replication and decreases tissue injury caused by the virus.

Interaction of SIAMP with IBV and blocking the virus binding to the embryos' epithelial cells were reported as the probable inhibitory mechanisms of the peptide [78] . Table 6 shows the characteristics of the peptides inhibiting the mammalian and avian coronaviruses binding.

The fusion or entry blocker peptides against other viruses from Coronaviridae family have been investigated in the literature. Wang et al., indicated that surfactin can effectively inhibit TGEV from entering the host cells [79] . Surfactin is a cyclic lipopeptide secreted by Bacillus subtilis, affects both the viruses and the cells as a membrane fusion inhibitor [79, 80] . Likewise, it could inhibit the fusion between the TGEV envelope and the host cell membrane in another study.

Surfactin inhibited the replication of TGEV and PEDV completely, and its oral administration also protected piglets from PEDV infection [80] . In another study, anti-PEDV properties of synthetic surfactin analogues were investigated. The SLP5 as a linear lipopeptide had lower cytotoxicity and similar antiviral activity, compared to the surfactin [81] . The PEDV entry was also blocked by a phage-displayed peptide through binding to the S protein, in Meng et al., study [82] . Anti-fusion and entry activities of S2 domain-based peptides against PEDV, FIPV, MHV and IBV have been described in the previous researches [35, [83] [84] [85] [86] . Moreover, the IBV infection in the host cells was inhibited by an antiviral peptide (As1) obtained from a medicinal plant. As1 binds to fusion and S protein of the virus and interferes with their function during IBV entry [87] . The characteristics of J o u r n a l P r e -p r o o f antiviral peptides with fusion or entry inhibitory activity against mammalian and avian viral strains are shown in Table 7 . The interaction of viperin with the N protein of PEDV led to interfering with viral replication or assembly [89] . Table 4 shows the characteristics of the viral replication inhibitor peptides.

The multiplication of PEDV was inhibited significantly by a cationic amphibian antimicrobial peptide in the host cells. The ability of Caerin1.1 to disrupt the integrity of the virus particles was mentioned as its inhibitory mechanism [90] . The characteristics of Caerin1.1 are shown in Table   5 .

The emergence or re-emergence of Coronaviridae family viruses and enhanced cross-species dissemination due to potential viral mutations are still real threats to the worldwide population.

Currently, there is no specific treatment for the majority of infections that caused by such viruses.

This study was the first review regarding antiviral peptides with activity against all studied viruses from Coronaviridae family. However, several peptides were found with different antiviral mechanisms. This review mainly aimed to summarize data regarding the peptides that can be applicable and provide relevant information to develop novel treatments. Our study suggests that 

The authors declare no conflict of interest. [17] G. Agarwal, R. Gabrani, Antiviral eptides: Identification and alidation, Int J Pept Res Ther. J o u r n a l P r e -p r o o f 

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

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Surfactin inhibits membrane fusion during invasion of epithelial cells by enveloped Viruses

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Not applicable.J o u r n a l P r e -p r o o f