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ISSN : 1229-1153(Print)
ISSN : 2465-9223(Online)
Journal of Food Hygiene and Safety Vol.36 No.5 pp.363-375

Role of Peptides in Antiviral (COVID-19) Therapy

Ramachandran Chelliah*, Eric Banan-Mwine Daliri, Fazle Elahi, Su-Jung Yeon, Akanksha Tyagi, Chae Rin Park, Eun Ji Kim, Jo kyoung Hee, Deog-Hwan Oh*
Department of Food Science and Biotechnology, College of Agriculture and Life Science, Kangwon National University, Chuncheon, South Korea
* Co Correspondence to: Ramachandran Chelliah, Department of Food Science and Biotechnology, College of Agriculture and Life Science, Kangwon National University, Chuncheon 24341, Korea Tel: +82-10-2556-2544; Fax:+82-33-250-6457 E-mail:
* Correspondence to: Deog-Hwan, Oh, Department of Food Science and Biotechnology, College of Agriculture and Life Science, Kangwon National University, Chuncheon 24341, Korea Tel: +82-10-5118-6457; Fax :+82-33-250-6457 E-mail:
August 22, 2021 September 23, 2021 September 28, 2021


Trends in the developing era to discover and design peptide-based treatments throughout an epidemic infection scenario such as COVID-19 could progress into a more efficient and low-cost therapeutic environment. However, the weakening of proteolysis is one downside of natural peptide drugs. But, peptidomimetics may help resolve this issue. In this review, peptide and peptide-based drug discovery were summarized to target one key entry mechanism of severe coronavirus pulmonary emboli syndrome (SARS-CoV-2), which encompasses the association of the host angiotensin-converting enzyme-2 (ACE2) receptor and viral spike (S) protein. Furthermore, the benefits of proteins, peptides and other possible actions that have been studied for COVID-19 through new peptide-based treatments are discussed in the review. Lastly, an overview of the peptide-based drug therapy environment is comprised of an evolutionary viewpoint, structural properties, operational thresholds, and an explanation of the therapeutic area.


    Around 108 million coronavirus disease cases (COVID- 19) were reported in 2019, and 2.4 million deaths up to date (COVID-19) were reported globally (Fig. 1)1,2). At the turn of the twentieth century, numerous zoonotic occurrences have contributed to epidemic outbreaks in humans, such as Influenza A, H1N1, H5N1, H7N9, Zika virus Ebola virus populations3). The epidemics attributable to affiliates in term of spread and survival of COVID family has been particularly prevalent, starting with the emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002- 2003, accompanied in 2012 by Middle East Coronavirus Respiratory Syndrome (MERS-CoV) and in late 2019 by SARS-CoV-2 (COVID-19)4). Based on the spikes protein’s and virulence factors, a large trimeric crown-like complex forming the namesake complex is a coronavirus family in humans. As noted in the microscopic examination, ‘corona’ (Fig. 2)5). The functional annotation on the coronavirus strains and their function of the spiked protein depends on the host species, and tissue tropism was found in bats. The SARSCoV, MERS-CoV, and SARS-CoV-2 were correlated with the current outbreaks, which share their entry receptors’ similarity, linking host cell post-translational. Still, coronaviruses may distinguish other COVID based on specific alterations like glycans or type of molecule binding. Whereas a) MERSCoV applies dipeptidyl peptidase-44 primarily (DPP4), which is responsible for the deprivation of incretins such as Glucagon-like peptide-1 (GLP-1) is a 30 or 31 amino acid long peptide hormone)., b) SARS-CoV and c) SARS-CoV- 2 can apply angiotensin-converting enzyme-2 (It is an enzyme attached to the cell membranes of cells in different human organs (lungs, arteries, heart, kidney, and intestines)) to penetrate human cells (ACE2) as the primary receptor (Fig. 2 and Fig. 3)6). In addition to perception and integration, the prior binding site was regulated by secondary pathways through signaling mediated by S protein, including C-type lectins and high-mannose glycans. It is also suggested that viral entry is possible through endocytosis7). The framework is arising in endosomes, with viral signal transduction. SARS-CoV and SARS-CoV-2 S protein are strongly glycosylated (It is an enzyme-directed chemical reaction that takes place in the Endoplasmic Reticulum (ER) and the Golgi Apparatus body (directs the protein binding) of the cell. Type I transmembrane glycoprotein of 180-200 kDa with its N-terminus existing on the Virus’s outer surface and a short C-terminal region of viral space inside the intramembrane. The S protein consists of subunits S1 and S2, which have a protease cleavage site. The S1 subunit facilitates the new promoter binding structure to ACE2, while the transmembrane machinery is present in the S2 region8). The comprised fusion peptides and domains of heptad-1 (HR1) and heptad-2 (HR2), which initiate the conjugation of the viral and outer membrane of the host cellbased on host receptor (Fig. 4)9,10). The S1 terminal forms the receptor-binding site (RBS) in the C terminal domain is composed of the amino acid residues.

    Mechanism of COVID viral infection

    After the SARS-CoV outbreak (2002-2003), the Virus was sequenced, and based on proteomic analysis; the receptor binding domain (RBD) was reported to contain 318-510 aminoacid, which represents to code for S proteins11). Likewise, the minimum binding domine (MBD) was described in combination with RBD based on a short loop structure which consists of 424-494 region containing Sproteins with 14 amino acids. Similarly, the SARS-CoV compared with the SARS-CoV 2 strain proteomic analysis revealed that the RBD sequence residue was found to be similar in the 331- 524 residue region12). Furthermore, based on the detailed proteomic reports, the conserved residues and sequence variation were observed in SARS-CoV 2, SARS-CoV 2, and MERS. The similarity in the sequence index of the S2 domine. Based on the review, the data on applying the drug target to the S2 domine region for the development of SARS-CoV therapeutics13).

    Previous studies indicate that after virus binding with the angiotensin-converting enzyme (ACE) receptor, the S protein present in the virus initiates host cell proteases14). The cleavage of the S1/S2 boundary releases the strain into the cell. Besides, the S2 subunit ( fusion peptide) domine also binds the host cell membrane with the virus. Further, the S2 cleavage site exposes the fusion peptide penetration to form six alpha-helix bundle, which assembles the host cell and virus membrane fusion, leads to the release of viral genetic (Fig. 5). The tissue-specific spread of proteases designed to progress the S protein, therefore, restricts the pathogenicity of different COVID, far beyond the primary receptor's cell and organ-specific position, angiotensinconverting enzyme 2 (ACE-2)15).

    The COVID targeted tissue expression occurs in many organs, but the higher ex-pression occurs in lunge-based alveolar epithelial cells and intestinal absorptive cells (simple columnar epithelial cells). The overexpression depends on ACE2 receptor-based glycoprotein leads to carboxy-peptidase (protease enzyme that hydrolyzes (cleaves) a peptide bond at the carboxy-terminal (Cterminal) end of a protein or peptide)16). Its main functions lead to convert vasoconstrictive and inflammatory peptide (Angiotension-2 into Angiotension-1-7 through the cleavage of the C - terminal; likewise, the angiotensin 1 converted into angiotensin (1-9)17).

    As for the year 2019-2020, many published research studies focused, initially on the history of outbreak, correlation of previous COVID strains with the current COVID-19 strain, and finally focused on therapeutic medicines to control the severance and to maintain the mortality, based on the therapeutic aspect, antibiotics were prescribed initially. Still, there is no effect on the COVID 19 virus. Eventually, the antibiotics helped control the bacterial infection as per the complication that emerged by COVID-1918). Further, the antimalarial drugs (chloroquine and hydroxychloroquine) showed effective treatment of SARS-CoV and other viruses such as HIV and Zika Virus. Few manuscripts were published on natural therapeutic peptides, which target the ACE2 - S protein ( protein-protein interaction)19). Hence the current review focus on the therapeutic peptides which were involved COVID treatment and further other application and importance of the developed therapeutic peptides were reviewed in detail. Further, the rapid multiplication of COVID-19 virus in kidney cells (Unpublished data).

    The invention of peptide therapy

    Peptides constitute a particular class of molecularly regulated but biochemically and therapeutically distinct pharmaceutical compounds. Peptides represent an opportunity for therapeutic intervention that closely imitates natural pathways as inherent signaling molecules for several physiological functions. Also, many peptide medicines are simply “replacements” that add or substitute peptide hormones in cases of insufficient or lacking endogenous concentration. This can be demonstrated by the isolation and initial therapeutic use of insulin in diabetics in the 1920s who did not produce enough hormone20). Currying adrenocorticotrophic hormone (ACTH) in livestock pituitary glands to treat different endocrine conditions in patients was accompanied by insulating peptides from whole livestock tissue21). Peptides have evolved as therapeutics over time and continue to grow as drug development and treatment paradigms (Table 1). In the first half of the 20thcentury, peptides, which were insulin-isolated and ACTH, gave life-saving medicines. In mid of the 90s, synthetic oxytocin and vasopressin were applied in clinical terms before sequence clarification, and peptides’ chemical syntheses became feasible. As the venom of arthropods and cephalopods has become recognized as a store of bioactive peptides, it has become a popular strategy for isolating natural products from exotic sources. The genomic age allowed many important peptide hormones to be recognized and molecularly characterized by the receptors, and industry and academia started to pursue new peptide ligands for such receptors. The enthusiasm for peptide therapy was later tempered by some native peptide limits, for example, short plasma halving life and low oral bioavailability. The short half-life of many peptide hormones modulates the hormone levels quickly but is complicated for several clinical developments. These peptide limitations were described elsewhere in detail22). We will concentrate on peptide characteristics recommended for human clinical development. Scientists have started using medicinal chemistry techniques to make candidates more like medicines by improving halflife, physiological stability, and receptor selectiveness. The clinic also provided peptide analogs of native hormones with enhanced medicinal properties.

    Oral bioavailability is another barrier to the production of peptide drugs: The enzymes designed to decompose amide bands of ingested proteins are effective at cleaving peptide hormones with the same interactions, and the high polarity and molecular weight of peptides severely restrict intestinal permeability. Since oral delivery is often desirable for promoting compliance with the patient, the need for injection decreases the appeal for evidence requiring ongoing, external care. Besides, the availability of an extensive combinatorial chemistry library and high percussion (HTS) technology has pendulum to small molecules aimed at peptide receptors in a new direction. The general challenge is to find a small molecule that mimics a peptide ligand’s receptor binding and selective modulation; small molecules are more appropriate for oral delivery and more accessible to produce than peptides. In the new screening library, the number and variety of scaffolds support the idea that leads molecules could be detected, optimized, and transformed into drugs. Structural biology applied an arrow to the carcass by delaminating main molecular interactions that any molecule could exploit at receptor active locations.

    In some cases, the small molecular approach has been better than in others. Small molecules are less effective than peptides in peptide receptors, and small molecules that function like antagonists can be detected more easily than agonists. For small molecular drug discovery, especially in class B GPCRs, the large ligand connecting site for some peptide GP CRS and extraordinary conforming changes needed for signal transduction are significant challenges23-26). Nevertheless, small molecules, including losartan and valsartan available orally, substituted peptide (SARENIN) as hypertension receptor blockers and other small molecules of the class A G protein-coupled receptors (GPCRs) for which no peptide drugs was marketed as Class A GPCRs (Table 2)

    Although resolving some problems in peptide medicines, the potential for liabilities associated with peptides, such as CYP inhibition leading to drug/drug interactions (DDI) and side effects arising from off-target binding, remains unchanged. While a significant discovery, small molecule ligands for peptide receptors are no substitute for peptide compounds. In recent times, the potential of peptide therapeutics has been further understood and nuanced (characterized).

    Novel synthetic drug strategies depend on drug absorption, distribution, metabolism, and excretion to be modulated through amino acid or backbone changes. Consequently, the characteristics of peptides previously seen as liabilities are no more problematic: for example, for some indications, injection is considered an acceptable route of administration partly because of the production of peps or depots, which reduce the injection frequency. Although several classes of oral medications for type 2 diabetes mellitus are available, the market of injectable GLP-1 peptide agonists has continued to expand since the exenatide approval in 2005, and several next-generation medicines candidates are currently in development27,28). Teriparatide, an osteoporosis-approved parathyroid truncated hormone, provides an anabolic mechanism of action that is distinct from orals and supports routine injection by oral bisphosphonates29). The Peptide drug applicants were produced against various molecular targets beyond the historically prevailing epithelial hormone receptors. The clinic contains peptides that disturb protein- protein interactions, target the tyrosine kinases receiver and inhibit intracellular targets30,31). Phage screen has recognized new peptides as the point of departure for scientific and medicinal chemical study and introduced new peptide scaffolds to the clinic32,33). This resulted in the production of therapeutic peptides in a complex and robust environment. In the USA, Europe, and Japan, more than 60 peptide products have been approved; more than 150 are under active clinical development. We will discuss molecular drug targets on COVID based on therapeutic peptides application (Table 3).

    Among several peptides, Mucroporin, (LFGLIPSLIGGLV SAFK) is one of the cati-onic Host Defense Peptide collected from a type of Scorpian Venom of Lychas mucronatus applied as a drug.

    Likewise, the four different mutation-based Mucroporin- M1 (LFRLIKS-LIKRLVSAFK) were applied as a more efficient drug than the raw peptide antiviral efficiency aginst SARS-CoV - 14.46 μg/mL; influenza H5N1 - 2.10 μg/mL; measles - 7.15 μg/mL34). The mucoprotein (M1) showed higher and immediate interaction with measles-based viral material and showed pre-treatment efficacy; besides, it also acts as a blocker towards molecular binding before the virus attachment to the host cells. The peptide mucoprotein (M1) binds with the virus outer-membrane showed higher electrostatic affinity, could block the interaction and distortion of the viral envelope, with act as an anti-viricidal effect against SARSCoV, MERS-CoV, and influenza H5N1 viruses35).

    Peptide target on the spike (s) glycoprotein

    The 36-residue peptide designed by Xia and colleagues EK1 (SLDQINVTFLDLEYEMKKLEEAIKKLEESYIDLKEL) act as a pan - CoV combined in-hibitor against SARS-CoV, MERS-CoV, and three SARS-related COVID-19 from As shown in Fig. 1 tested in bats, besides, the EK1 peptide targets on blocking the HR1 rho-binding domain to avoid the formation of fusion glycoprotein into a trimer of hairpins with a 6-helix bundle (6HB) core, which prevents the entry of the Virus into the host cell36).

    Additionally, EK1 acts as an intra-nasal drug for the treatment of human corona-virus OC43, which acts as an antiviral remedy for middle east respiratory syndrome-based coronavirus (MERS-CoV)37). This indicates that some single peptides can be applied against multiple therapeutic agents against different types and strains of coronavirus. This broad spectrum of antiviral (Anti-coV) function strongly indicates that EK1 will be an effective drug against the upcoming evolved SARS-CoV infection38). Recently as an alternative therapy, lipoprotein (EK1C4), synthesized through c terminal of peptide conjugate with a lipid moiety based on the serine and glycine (amino acid) as stronger binding affinity (-2.02). This binding affinity was enhanced based on the addition of polyethylene glycol (PEG) (EK1-GSGSGPEG4- Lipid)39).

    Similarly, based on lipid conjugation, antiviral therapy reported for HIV C34 inhibitor. Apart from EK1, HR2P-M2 peptides were designed as a drug target against 6HB core of H1 and 2 domains of middle east respiratory syndrome based coronavirus strain. The previous report conducted by channappanavar40) indicates that intranasal treatment of MERS-CoV with HR2P-M2 showed more potent antiviral efficacy, but the same peptide showed nil effect against SARS-CoV; these experimental outcomes showed the selective antiviral efficiency towards the COVID and other beta coronaviruses.

    Peptide targeting towards inhibition of endosomal/lysosomal acidification

    A novel peptide P9 (β-defensin-4) reported the potent and broad-spectrum antiviral activity with S2 subunit against MERS- CoV, which prevents the viral entry into the host cell based on the endocytosis41). The P9 possesses the peptide’s polycationic property (NGAICWGPCPTAFRQIG NCGHFKVRCCKIR), which triggers the micro-environment to prevent the acidification of endosomes. The potential hydrogen ion concentration (pH) of peptide plays a significant role in the activation of viral fusion with the endosomal membrane; if the acidification of the endosome was prevented, the endosomal fusion failed and leads to the uncoating mechanism of viral RNA release42). This broad spectral antiviral mechanism was also documented in SARS- CoV, different influenza virus strains, H1N1swin flue, H3N2, H5N1, H7N7, further the cytotoxicity (IC50) for P9 peptide was determined to be 380 μg/mL using the mammalian kidney cells. Thus, the broad therapeutic advantage re-opens a solution for the current COVID19 and upcoming mutated covid strains43).

    Host defense mechanism: protecting the receptor of the cell

    The primary point of COVID infection, based on the Angiotensin-converting enzyme 2 precursor (ACE2), which acts as a key entry point of viral into the host cell. The human α-defensin-derived natural lectin peptide HD5(1-9) (ATCYCRTGRCATRES-LSGVCEISGRLYRLCCR) synthesized plays a defensive role against COVID. Based on the structural and chemical properties of HD5 were predicted to recognized the inhibi-tion of SARS- CoV (Spike protein subunit) towards the host cell ACE244). But some research studies indicated that HD5 targeted specifically on S1 peptide subunit, instead targeted on the entire ACE2 receptor of the host cell. The higher binding strength of HD5 peptide towards the ACE2 receptor mainly depends on hydrogen bonding based on hydrophobic and hydrophilic interactions, which protects the host from viral attachment and infection45).

    Immunomodulatory based antiviral therapy

    The cyclic-based peptide (Rhesus θ-defensin-1 (RTD-1) synthesized from leukocytes of (Rhesus macaque (Macaca mulatta)), which substantially reduces the necrotizing bronchiolitis caused by SARS- CoV46). Besides, among the cytokines level, the interleukin -6 (IL6), keratinocyte, and granulocyte (white blood cells in the innate immune system pigeonholed by the occurrence of specific granules in their cytoplasm47). They are also called polymorphonuclear leukocytes (PMN, PML, or PMNL)) in lung tissue homogenates, thus RTD- 1 peptide act as immuno-modulatory effector compound through the production of proinflammatory based cytokines response in eradicating SARS- CoV48).

    Likewise, the lactoferrin (LF) is a globular glycoprotein (molecular mass - 80 kDa) antiviral peptide, act as an ironbinding protein present in the different mucosal secreted matrix (milk, saliva, tears, and nasal secretions), which has a vital role in the function towards immune enhancement. Besides, the lactoferrin act as a multifunctional (protein of the transferrin family) mechanism (bacteriocide, fungicide)49). The critical part of antiviral therapy for humans and animals-based Virus (containing DNA or RNA genetic material) is that the LF acts as an immune enhancement. Further, LF functions as a viral binding inhibitor in the cellular receptors50). LF is present in human breast milk as one of the major constituents. Hence breast milk will be one of the natural remedies as antiviral therapy; most of the proven research aspects indicate that LF has multifunction therapeutic target against HCV, HSV, HIV, polio-, and the rotavirus. The significant spread of coronavirus through the oral and nasal, in which the LF binds directly to the virus particle. Hence it may act as an effective remedy against the coronavirus51). Further, LF can be applied as an individual drug or drug conjugate (synergetically functions as a combined antiviral drug with the conventional medicine)52). This will avoid drug resistance mechanisms caused by mutated strains.

    Antiviral peptide therapy’s towards future directions

    Globally, due to the pandemic condition's emergency, the need for an effective drug for controlling infectious disease (COVID-19 and the mutated strains of COVID 1953). In search of the most effective antiviral agent against COVID -19, we believe natural antiviral protein could be a potential class of antiviral drug towards COVID-1954). It is an exciting and impressive discovery that how the peptide (short amino acid) acts on the Virus and controls the viral mechanism, and preventing the receptor binding; likewise specific target and selectivity of the peptide depends on the viral strain. From this review, we like to bring attention to the application of Antiviral peptide against COVID viral envelope, HR2P targets the viral S protein, which mediates the binding mechanism, EK1, and lipid binding Ek1 (lipopeptide), which blocks the HR1 domine (S2 protein) and P9 peptide stops the acidification of the endosome and prevent the viral RNA release34). Besides the antiviral protein towards protecting the host. RTD -1 act as an immunomodulatory, which triggers proinflammatory cytokines, HD5 binds to the ACE 2receptor, which prevent the viral attachment36). Recent findings show the more substantial proof on host serine protease (TMPRSS2) is one of the multifunction S proteins against SARS - CoV, which prevents the viral membrane fusion mechanism41).

    Furthermore, the novel Sprotein furin (cleavage site) and CD147 based viral entry pathway were prevented SARS - CoV virulence. These are the major peptides based compounds, which targets different site. Furthermore, the combined therapy of antiviral peptides could provide a promising treatment strategy that will further study their synergetic efficacy towards clinical studies. As per the United states of Food and Drug Administration, a total of 36 amino acids based combination based inhibitor was approved in 2003 for the treatment against HIV (Human immunodeficiency virus) in combination with other synthetic-based antiviral drug therapy. In China, some of the studies were ongoing to prevent the viral-based HR1 (viral envelope) based glycoprotein-based clinical trial (3rd Phase)55). Further, the clinical trial of antiviral peptide therapy against covid could effectively replace the drug therapy discovery, leading to the development of operation warp speed by the United States government (April 2020) for the Covid-19 vaccine therapeutic and diagnostic development56).

    Peptides have formed a specific therapeutic role from humble beginnings as substances extracted from animal glands will remain a significant aspect of the therapeutic sector. By expanding into new applications and therapeutic goals, using new chemical approaches to increase molecular diversity and technologically improved medicinal properties, peptide-based pharmaceuticals have kept pace with innovation and progress. We expect that work will continue to view new opportunities for peptides. Peptides are a convenient baseline for discovering drugs as the catalog of peptide medicines used regularly in the medical practice is an endogenous ligand for peptide hormone towards targeted receptors.

    The future application of peptide-based drugs to new targets continues to be extended. Study. Throughout the early phase, human trials or in preclinical models of infection, many peptide-added targets for which no medications have been authorized have shown as for the therapeutic values57). Novel peptide therapies are still available. To control the properties of drug targeting such as permeability and stability, hits are often optimized. For this purpose, an outline of the peptide chemical toolbox shows the different options. Cyclic peptides have received particular attention and modifications to achieve surface integration that bridges the conventional pharmacology gap. Sequence motives and scaffolds, which can be applied in cells, known as cell invading peptides, are primarily interest for groundbreaking peptide-based medicines.

    Refinements in peptide analyzing and computational engineering will continue supporting drug development58-61). Improved understanding of the molecular basis for human genetic disorders will produce novel possible therapy leads. De-orphanizing poorly defined peptide targets will promote research programs for new membrane-ligand pairing62). Besides, new methods to the development, production, and development of peptide drugs will expand the versatility of the unique class of molecules. Initiatives will be underway to boost the oral disponibility of peptide clinical applications via increased drug stabilization in the gastrointestinal tract and peptide- formulation by enhancing the central nervous system’s absorption through combining them with transporter molecules or nanotubes. We will refer you to other chapters on this topic for further information on developments in peptide chemistry and conjugation. The final sequence of mini-examinations complements this set well by providing insights into halves of life extension, formula considerations, and changes necessary to produce the new peptide generation.


    The Antiviral peptide is structurally and biochemical versatile for developing the molecular model for the generation of therapeutic drugs against COVID-19. The scope of antiviral peptide molecules will be strengthened by modern peptide therapeutics, design, and half-life enhancement strategies. Initiatives have been undertaken to increase the oral availability of peptide therapeutics by growing the stabilization of drugs in the intestinal system and by implementing peptides with permeability enhancers and enhancing the availability of peptides in the COVID-19 by conjugating or delivering peptides through nanoparticles via carrier molecules. Therefore the objectives of the article have short and long-term parts. Regarding the short-term to ensure efficient and safe treatment against COVID-19 and further decrease the human mortality rate, which has been increased exponentially based on viral infection. Secondly, the drugs we provide as a treatment to prevent disease spread can be designed to act dually as an immunomodulatory. A longterm objective to research is needed to continue till the human trial to bring back the natural substituents against COVID19 and other upcoming infections. Through which our future generation’s health and safety can be safeguarded, this will enhance the social welfare of humans.


    COVID-19와 같은 전염병 감염 시나리오 전반에 걸쳐 펩타이드 기반 치료법을 발견하고 설계하는 개발 시대의 추세는 보다 효율적이고 저렴한 치료 환경으로 발전할 수 있습니다. 결과적으로, 그들의 단백질 분해 약화는 천연 펩타이드 약물의 단점 중 하나입니다. 펩티도미메틱스는 이 단점을 해결하는 데 도움이 될 수 있습니다. 이 리뷰 에서 펩타이드 및 펩타이드 기반 약물 발견은 숙주 안지 오텐신 전환 효소-2(ACE2) 수용체 및 바이러스 스파이크 (S)단백질의 연관성을 포함하는 중증 코로나바이러스 폐 색전 증후군(SARS-CoV-2)의 주요 진입 기전 중 하나를 표적으로 요약했습니다. 또한, 펩타이드 기반의 새로운 치 료법을 통해 COVID-19에 대해 연구된 단백질, 펩타이드 및 기타 가능한 조치의 이점을 다룹니다. 그리고 펩타이 드 기반 약물 치료 환경의 개요는 진화적 관점, 구조적 특 성, 작동 한계값 및 치료 영역에 대한 설명으로 구성된다


    Chelliah Ramachandran is grateful for the financial support from National Research Foundation of Korea (NRF) 2018007551 and this work was partially supported (Fazle Elahi) by Korea Research Fellowship (KRF) Program (Grant No: 2020H1D3A1A02081423) through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT, Republic of Korea.



    (a) Data on this page is taken from the COVID-19 Dashboard on 15 February, 2021 and (b) Data collected on 23 September, 2021 by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU) (


    Transmission electron microscopic image of SARS-CoV-2 (which shows corona viral particles’ presence in the cross-sections of the rough endoplasmic reticulum (RER). These spherical structures were surrounded by dark layers, which are the spikes on coronavirus particles). Schematic representation general structure of SARS-CoV’s and host cell entry receptor ACE2.


    Transmission electron microscopic image of SARS-CoV-2 (which shows corona viral particles’ presence in the crosssections of the rough endoplasmic reticulum (RER). These spherical structures were surrounded by dark layers, which are the spikes on coronavirus particles).


    A 2 Dimensional-representation of the critical domains of the COVID protein. The spike (S) protein was combined with the two subunits: S1 and S2. The S1 domain poses the N terminal domain (NTD), the C terminal domain (CTD), and it is responsible for recognition and binding to the host cell receptor. The S2 domain, responsible for membrane fusion, contains the Fusion protein (FP), heptad repeat 1 (HR1), heptad repeat HR2, the transmembraneTM, and cytoplasmic tail regions (CP tail). Two cleavage sites were indicated with arrows. The major peptide-based therapeutics indicated below are associated S protein regions. Kilodalton (kDa), Severe Acute Respiratory Syndrome (SARS).


    Mechanism of actions of Antiviral protein with potential anti-SARS-CoV-2 activities. Numerous antiviral protein target the major morphology components of the Virus to exert antiviral effects: mucroporin-M1 (Cationic Peptide), which mainely acts by disrupting viral envelope, HR2P-M2 targets the viral Spike protein-mediated fusion, EK1 and EK1C4 block the HR1 subunit domain of viral S2 subunit and P9 peptide act towards stopping late host endosome cell layer degradation (acidification) and thus preventing viral RNA release. Anti-viral peptide confers antiviral protection to the host: RTD-1 is a potent antiviral immuno-modulatory to initiates immune enhancement, and HD5 adheres and protects ACE2 from viral specification docking.


    List of exRNA-EVs and their description and functional roles

    Small molecule drugs act on peptide receptors

    Updated peptide-based therapeutic against SARS-CoV and SARS-CoV-2.34-41)


    1. Alqahtani, J.S., Oyelade, T., Aldhahir, A.M., Alghamdi, S.M., Almehmadi, M., Alqahtani, A.S., Quaderi, S., Mandal, S., Hurst, J.R., Prevalence, severity and mortality associated with COPD and smoking in patients with COVID-19: a rapid systematic review and meta-analysis. PLoS One, 15, e0233147 (2020).
    2. Johns Hopkins Univ., (2021, September 23). Global Cases by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU). Retrieved from
    3. Graham, B.S., Sullivan, N.J., Emerging viral diseases from a vaccinology perspective: preparing for the next pandemic. Nat. immunol., 19, 20-28 (2018).
    4. Biegańska-Banaś, J.M., Makara-Studzińska, M., Coping strategies among nurses during the COVID-19 outbreak. Problemy Pielęgniarstwa, 28, 1-11 (2020).
    5. Goldsmith, C.S., Miller, S.E., Martines, R.B., Bullock, H.A., Zaki, S.R., Electron microscopy of SARS-CoV-2: a challenging task. The Lancet, 395, e99 (2020).
    6. Sanchis-Gomar, F., Lavie, C.J., Perez-Quilis, C., Henry, B.M., Lippi, G., Angiotensin-converting enzyme 2 and antihypertensives (angiotensin receptor blockers and angiotensin- converting enzyme inhibitors) in coronavirus disease 2019. Mayo Clin. Proc., 95, 1222-1230 (2020).
    7. Sharma, R.K., Stevens, B.R., Obukhov, A.G., Grant, M.B., Oudit, G.Y., Li, Q., Richards, E.M., Pepine, C.J., Raizada, M.K., ACE2 (Angiotensin-Converting Enzyme 2) in cardiopulmonary diseases: ramifications for the control of SARSCoV- 2. Hypertension, 76, 651-661 (2020).
    8. Outlaw, V.K., Bovier, F.T., Mears, M.C., Cajimat, M.N., Zhu, Y., Lin, M.J., Addetia, A., Lieberman, N.A., Peddu, V., Xie, X., Shi, P.Y., Greninger, A.L., Gellman, S.H., Bente, D.A., Moscona, A., Porotto, M., Inhibition of coronavirus entry in vitro and ex vivo by a lipid-conjugated peptide derived from the sars-cov-2 spike glycoprotein hrc domain. mBio, 11, (2020).
    9. VanPatten, S., He, M., Altiti, A., Cheng, K.F., Ghanem, M.H., Al-Abed, Y., Evidence supporting the use of peptides and peptidomimetics as potential SARS-CoV-2 (COVID-19) therapeutics. Future Med. Chem., 12, 1647-1656 (2020).
    10. Beniac, D.R., Booth, T.F., 2010. Structural molecular insights into SARS coronavirus cellular attachment, entry and morphogenesis, In Molecular Biology of the SARSCoronavirus. Springer, Berlin, Heidelberg, pp. 31-43
    11. Zhao, G.P., SARS molecular epidemiology: a Chinese fairy tale of controlling an emerging zoonotic disease in the genomics era. Philos. Trans. R. Soc. Lond B Biol. Sci., 362, 1063-1081 (2007).
    12. Anand, K.B., Karade, S., Sen, S., Gupta, R.M., SARS-CoV- 2: camazotz's curse. Med. J. Armed Forces India, 76, 136- 141 (2020).
    13. Gandhi, L., Rodriguez-Abreu, D., Gadgeel, S., Esteban, E., Felip, E., De Angelis, F., Domine, M., Clingan, P., Hochmair, M.J., Powell, S.F., Cheng, S.Y.S, Bischoff, H.G., Peled, N., Grossi, F., Jennens, R.R., Reck, M., Hui, R., Garon, E.B., Boyer, M., Rubio-Viqueira, B., Novello, S., Kurata, T., Gray, J.E., Vida, J., Wei, Z., Yang, J., Raftopoulos, H., Pietanza, M.C., Garassino, M.C., Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N. Engl. J. Med., 378, 2078-2092 (2018).
    14. Zhang, H., Penninger, J.M., Li, Y., Zhong, N., Slutsky, A.S., Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV- 2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med., 46, 586-590 (2020).
    15. Lohi, H., Kujala, M., Makela, S., Lehtonen, E., Kestila, M., Saarialho-Kere, U., Markovich, D., Kere, J., Functional characterization of three novel tissue-specific anion exchangers SLC26A7,-A8, and-A9. J. Biol. Chem., 277, 14246-14254 (2002).
    16. Wei, C., Wan, L., Yan, Q., Wang, X., Zhang, J., Yang, X., Zhang, Y., Fan, C., Li, D., Deng, Y., Sun, J., Gong, J., Yang, X., Wang, Y., Wang, X., Li, J., yang, H., Li, H., Zhang, Z., Wang, R., Du, P., Zong, Y., Yin, F., Zhang, W., Wang, N., Peng, Y., Lin, H., Feng, J., Qin, C., Chen, W., Gao, Q., Zhang, R., Cao, Y., Zhong, H., HDL-scavenger receptor B type 1 facilitates SARS-CoV-2 entry. Nat. Metab., 2, 1391- 1400 (2020).
    17. Ye, M., Wysocki, J., Gonzalez-Pacheco, F.R., Salem, M., Evora, K., Garcia-Halpin, L., Poglitsch, M., Schuster, M., Batlle, D., Murine Recombinant Angiotensin-Converting Enzyme 2: Effect on Angiotensin II-Dependent Hypertension and Distinctive Angiotensin-Converting Enzyme 2 Inhibitor Characteristics on Rodent and Human Angiotensin- Converting Enzyme 2. Hypertension, 60, 730-740 (2012).
    18. Drożdżal, S., Rosik, J., Lechowicz, K., Machaj, F., Kotfis, K., Ghavami, S., & Łos, M. J., FDA approved drugs with pharmacotherapeutic potential for SARS-CoV-2 (COVID- 19) therapy. Drug Resist. Updat., 100719 (2020).
    19. Pillaiyar, T., Wendt, L.L., Manickam, M., Easwaran, M., The recent outbreaks of human coronaviruses: A medicinal chemistry perspective. Med. Res. Rev., 41, 72-135 (2021).
    20. Banting, F.G., Best, C.H., Collip, J.B., Campbell, W.R., Fletcher, A.A., Pancreatic Extracts in The Treatment of Diabetes Mellitus. Diabetes, 5, 69-71 (1956).
    21. Elkinton, J.R., Hunt, A.D., Godfrey, L., McCrory, W.; Rogerson, A.; Stokes, J. Effects of pituitary adrenocorticotropic hormone (ACTH) therapy. JAMA, 141, 1273-1279 (1949)
    22. Lau, J.L., Dunn, M.K., Therapeutic peptides: Historical perspectives, current development trends, and future directions. Bioorganic & medicinal chemistry, 26, 2700-2707 (2018).
    23. Hollenstein, K., de Graaf, C., Bortolato, A., Wang, M.W., Marshall, F.H., Stevens, R.C., Insights into the structure of class B GPCRs. Trends in pharmacological sciences, 35, 12- 22 (2014).
    24. Agoulnik, A.I., Agoulnik, I.U., Hu, X., Marugan, J., Synthetic non?peptide low molecular weight agonists of the relaxin receptor 1. Br. J. Pharmacol., 174, 977-989 (2017).
    25. Mishra, R.K., Shum, A.K., Platanias, L.C., Miller, R.J., Schiltz, G.E., Discovery and characterization of novel smallmolecule CXCR4 receptor agonists and antagonists. Sci. Rep., 6, 1-9 (2016).
    26. Sacks, L.V., Shamsuddin, H.H., Yasinskaya, Y.I., Bouri, K., Lanthier, M.L., Sherman, R.E., Scientific and regulatory reasons for delay and denial of FDA approval of initial applications for new drugs, 2000-2012. JAMA, 311, 378-384 (2014).
    27. Hollenberg, N.K., Williams, G.H., Burger, B., Ishikawa, I., Adams, D.F., Blockade and stimulation of renal, adrenal, and vascular angiotensin II receptors with 1-Sar, 8-Ala angiotensin II in normal man. J. Clin. Invest., 57, 39-46 (1976).
    28. Mullard, A., Once-yearly device takes on daily and weekly diabetes drugs. Nat. Biotechnol. 32, 1178 (2014).
    29. Camacho, P.M., Petak, S.M., Binkley, N., Clarke, B.L., Harris, S.T., Hurley, D.L., Kleerekoper, M., Lewiecki, E.M., Miller, P.D., Narula, H.S., Pessah-Pollack, R., Tangpricha, V., Wimalawansa, S.J., Watts, N.B., American Association of Clinical Endocrinologists and American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis — 2016—Executive Summary. Endocr. Pract., 22, 1111-1118 (2016).
    30. Stupp, R., Hegi, M.E., Gorlia, T., Erridge, S.C., Perry, J., Hong, Y.K., Aldape, K.D., Lhermitte, B., Pietsch, T., Grujicic, D., Steinbach, J.P., Wick, W., Tarnawski, R., Nam, D.H., Hau, P., Weyerbrock, A., Taphoorn, M.J., Shen, C.C., Rao, N., Thurzo, L., Herrlinger, U., Gupra, T., Kortmann, R.D., Adamska, K., McBain, C., Brandes, A.A., Tonn, J.C., Schnell, O., Wiegel, T., Kim, C.Y., Nabors, L.B., Reardon, D.A., van den Bent, M.J., Hicking, C., Markivskyy, A., Picard, M., Wller, M., Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol., 15, 1100-1108 (2014).
    31. Chang, Y.S., Graves, B., Guerlavais, V., Tovar, C., Packman, K., To, K.H., Olson, K.A., Kesavan, K., Gangurde, P., Mukherjee, A., Baker, T., Darlak, K., Elkin, C., Filipovic, Z., Qureshi, F.Z., Cai, H., Berry, P., Feyfant, E., Shi, X.E., Horstick, J., Annis, D.A., Manning, A.M., Fotouhi, N., Nash, H., Vassilev, L.T., Sawyer, T.K., Stapled α− helical peptide drug development: A potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy. Proc. Natl. Acad. Sci. U S A., 110, E3445-E3454 (2013).
    32. Meerovitch, K., Torkildsen, G., Lonsdale, J., Goldfarb, H., Lama, T., Cumberlidge, G., Ousler III, G.W., Safety and efficacy of MIM-D3 ophthalmic solutions in a randomized, placebo- controlled Phase 2 clinical trial in patients with dry eye. Clin. Ophthalmol., 7, 1275-1285 (2013).
    33. Birk, A.V., Liu, S., Soong, Y., Mills, W., Singh, P., Warren, J.D., Seshan, S.V., Pardee, J.D., Szeto, H.H., The mitochondrial- targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. J. Am. Soc. Nephrol., 24, 1250-1261 (2013).
    34. Li, Q., Zhao, Z., Zhou, D., Chen, Y., Hong, W., Cao, L., Yang, J., Zhang, Y., Shi, W., Cao, Z., Wu, Y., Yan, H., Li, W., Virucidal activity of a scorpion venom peptide variant mucroporin-M1 against measles, SARS-CoV and influenza H5N1 viruses. Peptides, 32, 1518-1525 (2011).
    35. Jaiswal, G., Kumar, V., In-silico design of a potential inhibitor of SARS-CoV-2 S protein. PLoS One, 15, e0240004 (2020).
    36. Xia, S., Zhu, Y., Liu, M., Lan, Q., Xu, W., Wu, Y., Ying, T., Liu, S., Shi, Z., Jiang, S., Lu, L., Fusion mechanism of 2019- nCoV and fusion inhibitors targeting HR1 domain in spike protein. Cell. Mol. Immunol., 17, 765-767 (2020).
    37. Xu, J., Jia, W., Wang, P., Zhang, S., Shi, X., Wang, X., Zhang, L., Antibodies and vaccines against Middle East respiratory syndrome coronavirus. Emerg. Microbes infect., 8, 841-856 (2019).
    38. Xia, S., Yan, L., Xu, W., Agrawal, A.S., Algaissi, A., Tseng, C.T.K., Wang, Q., Du, L., Tan, W., Wilson, I.A., Jiang, S., Yang, B., Lu, L., A pan-coronavirus fusion inhibitor targeting the HR1 domain of human coronavirus spike. Sci. Adv., 5, eaav4580 (2019).
    39. Izzo, C., Grillo, F., Murador, E., Improved method for determination of high-density-lipoprotein cholesterol I. Isolation of high-density lipoproteins by use of polyethylene glycol 6000. Clin. Chem., 27, 371-374 (1981).
    40. Channappanavar, R., Lu, L., Xia, S., Du, L., Meyerholz, D.K., Perlman, S., Jiang, S., Protective effect of intranasal regimens containing peptidic Middle East respiratory syndrome coronavirus fusion inhibitor against MERS-CoV infection. J. Infect. Dis., 212, 1894-1903 (2015).
    41. Schutz, D., Ruiz-Blanco, Y.B., Munch, J., Kirchhoff, F., Sanchez- Garcia, E., Muller, J.A., Peptide and peptide-based inhibitors of SARS-CoV-2 entry. Adv. Drug Deliv. Rev., 167, 47-65 (2020).
    42. Baik, M., The mechanism of small molecule viral fusion inhibitors. PhD thesis, University of Alabama at Birmingham, Birmingham, Alabama (2015).
    43. Dawood, A.A., Mutated COVID-19 may foretell a great risk for mankind in the future. New Microbes and New Infections, 35, 100673 (2020).
    44. Rathod, S.B., Prajapati, P.B., Punjabi, L.B., Prajapati, K.N., Chauhan, N., Mansuri, M.F., Peptide modelling and screening against human ACE2 and spike glycoprotein RBD of SARS-CoV-2. In silico pharmacol., 8, 1-9 (2020).
    45. Yang, D., Application of Nanotechnology in the COVID-19 Pandemic. Int J. Nanomedicine, 16, 623-649 (2021).
    46. Memariani, H., Memariani, M., Therapeutic and prophylactic potential of anti-microbial peptides against coronaviruses. Ir. J. Med. Sci., 189, 1153-1154 (2020).
    47. Henson, P.M., Bratton, D.L., 2009. Phagocyte-Pathogen Interactions: Macrophages and the Host Responses to Infection, American Society for Microbiology, Washington, D.C, DC, USA, pp. 341-365
    48. Sousa, F.H., Casanova, V., Stevens, C., Barlow, P.G., 2016. Antiviral host defence peptides. Host Defense Peptides and Their Potential as Therapeutic Agents, Springer, Cham, pp. 57-94.
    49. Albar, A.H., Almehdar, H.A., Uversky, V.N., Redwan, E.M., Structural heterogeneity and multifunctionality of lactoferrin. Curr. Protein Pept. Sci., 15, 778-797 (2014).
    50. Smith, S.A., Kotwa, G.J., Immune response to poxvirus infections in various animals. Crit. Rev. Microbiol., 28, 149- 185 (2002).
    51. Hodinka, R. L., Respiratory RNA viruses. Microbiol. Spectr., 4, (2016).
    52. Wang, H., Chen, Q., Zhou, S., Carbon-based hybrid nanogels: a synergistic nanoplatform for combined biosensing, bioimaging, and responsive drug delivery. Chem. Soc. Rev., 47, 4198-4232 (2018).
    53. El-Subbagh, N.H., Rabie, R., Mahfouz, A.A., Aboelsuod, K.M., Elshabrawy, M.Y., Abdelaleem, H.M., Elhammady, B.E., Abosaleh, W., Salama, L.A., Badreldeen, S., Yasser, M., Elgaml, A., Characteristic Features of Coronavirus Disease- 2019 (COVID-19) Pandemic: Attention to the Management and Control in Egypt. Journal of Disaster Research, 16, 70-83 (2021).
    54. Dayrit, Fabian M., Mary T., Newport, M.D., 2020. The Potential of Coconut Oil as an Effective and Safe Antiviral Agent Against the Novel Coronavirus (nCoV-2019), pp. 1-4.
    55. Sun, B., Jia, L., Liang, B., Chen, Q., Liu, D., Phylogeography, transmission, and viral proteins of Nipah virus. Virol. Sin., 33, 385-393 (2018).
    56. Zhang, Q., Wang, Y., Qi, C., Shen, L., Li, J., Clinical trial analysis of 2019?nCoV therapy registered in China. J. Med. Virol., 92, 540-545 (2020).
    57. Abbara, A., Jayasena, C.N., Christopoulos, G., Narayanaswamy, S., Izzi-Engbeaya, C., Nijher, G.M.K., Comninos, A.N., Peters, D., Buckley, A., Ratnasabapathy, R., Prague, J.K., Salim, R., Lavery, S.A., Bloom, S.R., Szigeti, M., Ashby, D.A., Trew, G.H., Dhillo, W.S., Efficacy of kisspeptin- 54 to trigger oocyte maturation in women at high risk of ovarian hyperstimulation syndrome (OHSS) during in vitro fertilization (IVF) therapy. J. Clin. Endocrinol. Metab., 100, 3322-3331 (2015).
    58. Ling, L.L., Schneider, T., Peoples, A.J., Spoering, A.L., Engels, I., Conlon, B.P., Mueller, A., Schaberle, T.F., Hughes, D.E., Epstein, S., Jones, M., Lazardes, L., Steadman, V.A., Cohen, D.R., Felix, C.R., Fetterman, K.A., Millett, W.P., Nitti, A.G., Zullo, A.M., Chen, C., Lewis, K., A new antibiotic kills pathogens without detectable resistance. Nature, 517, 455-459 (2015).
    59. Motley, J.L., Stamps, B.W., Mitchell, C.A., Thompson, A.T., Cross, J., You, J., Powell, D.R., Stevenson, B.S., Cichewicz, R.H., Opportunistic sampling of roadkill as an entry point to accessing natural products assembled by bacteria associated with non-anthropoidal mammalian microbiomes. J. Nat. Prod., 80, 598-608 (2017).
    60. Lavergne, V., Harliwong, I., Jones, A., Miller, D., Taft, R.J., Alewood, P.F., Optimized deep-targeted proteotranscriptomic profiling reveals unexplored Conus toxin diversity and novel cysteine frameworks. PNAS, 112, E3782-E3791 (2015).
    61. Romere, C., Duerrschmid, C., Bournat, J., Constable, P., Jain, M., Xia, F., Saha, P.K., Del Solar, M., Zhu, B., York, B., Sarkar, P., Rendon, D.A., Gaber, M.W., LeMaire, S.A., Coselli, J.S., Milewicz, D.M., Sutton, V.R., Butte, N.F., Moore, D.D., Chopra, A.R., Asprosin, a fasting-induced glucogenic protein hormone. Cell, 165, 566-579 (2016).
    62. Walther, A., Riehemann, K., Gerke, V., A novel ligand of the formyl peptide receptor: annexin I regulates neutrophil extravasation by interacting with the FPR. Mol. cell, 5, 831- 840 (2000).
    63. Figshare, (2021, September 23). Rapid multiplication of COVID Virus. Retrieved from