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Year : 2023  |  Volume : 55  |  Issue : 1  |  Page : 53--58

Peptides and peptidomimetics as a therapeutic candidate for the treatment of COVID-19: A brief review

J Kumaravel, Harvinder Singh, Sukhmeet Kaur, Ajay Prakash, Bikash Medhi 
 Department of Pharmacology, PGIMER, Chandigarh, India

Correspondence Address:
Bikash Medhi
Department of Pharmacology, PGIMER, Chandigarh


Novel SARS-CoV-2 (COVID-19) is affecting worldwide as declared pandemic by the WHO. Various repositioning and novel therapeutic agents are being evaluated under different clinical setups; however, there is no promising therapeutic agent reported to date. Small molecules like peptides have their popularity as their specificity, delivery, and synthesizability as promising therapeutic agents. In this study, we have reviewed the published literature describing peptide designing, in silico binding mode, antiviral activity, preventive measures, and in vivo assessments. Here, we reported all the results which are promising against SARS-CoV-2 as therapeutic and preventive (vaccine candidates), and their status in the drug development process.

How to cite this article:
Kumaravel J, Singh H, Kaur S, Prakash A, Medhi B. Peptides and peptidomimetics as a therapeutic candidate for the treatment of COVID-19: A brief review.Indian J Pharmacol 2023;55:53-58

How to cite this URL:
Kumaravel J, Singh H, Kaur S, Prakash A, Medhi B. Peptides and peptidomimetics as a therapeutic candidate for the treatment of COVID-19: A brief review. Indian J Pharmacol [serial online] 2023 [cited 2023 Oct 3 ];55:53-58
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Severe acute respiratory syndrome coronavirus disease caused by SARS-CoV-2, reported from Wuhan, China, is rapidly spreading over the world in a short period. It infected over 37 million people and killed over 793,773 people, and the number of cases is growing by the day.[1] Globally, it has a case fatality rate of 3.5.[2] There is no promising therapeutic agent discovered to date, even though many products are undergoing fast-track clinical trials for efficacy and safety assessment.

COVID-19 management is based on the patient's clinical status, including mild, moderate, and severe diseases.[3] The mild disease requires symptomatic treatment and isolation at home. Moderate disease generally requires treatment based on the negatively affected lung and oxygenation. The severe illness necessitates hospitalization. Azithromycin, remdesivir, favipiravir, steroids, and interleukin-6 antagonists (tocilizumab and itolizumab) are commonly used drug candidates for the management of COVID-19.[3],[4],[5] Sarma et al., the study's authors, mentioned the use of steroids based on the severity categories of the patients, and they concluded that steroid administration might have been beneficial in COVID-19 patients.[6] Although there are symptomatic treatments available, lacks of satisfactory or efficacious therapeutic agents have not been reported. However, drug discovery and development are strenuous and time-consuming for small molecules.

Peptide-based therapeutic approaches are one of those treatment options being investigated around the world for different diseases.[7],[8] Peptides are smaller protein fragments that have some advantages over other therapeutic products in terms of ease of synthesis, feasibility for rapid clinical transformation, and cost-effectiveness.[9],[10] Peptides can be designed for a variety of target-specific sequences known as epitopes, which can be defined and classified as follows:

An epitope is an antigen determinant or a part/residue of an antigen that binds to an antibody via its paratope counterpart. T-cell epitopes are peptides derived from protein antigens presented on an antigen-presenting cell by major histocompatibility complex molecules and recognized by T-cell receptors. Peptides or residues on the surface of proteins that bind to antibodies are referred to as B-cell epitopes.[11],[12] Protein epitopes are classified into two types based on structure and interaction [Table 1].{Table 1}

Other classifications of peptides are based on the number of amino acids or residues, i.e., short and polypeptides. Peptides have short chains of 2–50 amino acids linked by peptide bonds which include dipeptides, tripeptides, tetrapeptides, and oligopeptides. A polypeptide is a fifty-amino acid peptide chain that is long, continuous, and unbranched.[13]

Peptides are further divided into various groups based on their origins and functions. Sources of peptides include plant, bacterial, fungal, amphibian/skin, venom, brain, endocrine, gastrointestinal, cardiovascular, renal, respiratory, and neurotrophic.[14] The functional classification consists of neuropeptide, lipopeptide, and peptide hormone.

As technology advances, structural targets for SARS-CoV-2 have been validated and are now readily accessible in a resolved form for early drug discovery and development.[15] Spike protein, heptad repeat 1 (HR1) and HR2 assembly, main protease (Mpro and 3CLpro), RNA-dependent RNA polymerase, and nonstructural protein 15 of SARS CoV-2 have been described by Prajapat et al., paving the way for the evolution of effective COVID-19 drug discovery and designing approach.[16],[17],[18]

Peptides and peptide-based treatment approaches can target the interaction between the host angiotensin-converting enzyme 2 (ACE2) receptor and the viral spike (S) protein of SARS-CoV-2. The peptide's principal mechanism is to block the S protein's receptor-binding region from interacting with ACE2 receptors.[9],[10]

This review article mainly focused on the scope and current status of peptides, peptidomimetics, and peptide-based vaccines as therapeutic candidates for COVID-19. Only a few studies have investigated the role of peptides and peptide-based agents as potential COVID-19 therapeutics. Due to a lack of data on this topic, we gathered evidence of the role of peptides and peptide-based agents in COVID-19 management from all drug discovery platforms, including in silico, in vitro, in vivo, and clinical trials.

In silico studies targeting S1: Angiotensin- converting enzyme 2 interaction (therapeutic intention)

[Table 2] displays the data on designed peptides (therapeutic/vaccine) against SARS-CoV-2. The majority of these peptides targeted the S1:ACE2 interaction, particularly the receptor-binding domain (RBD) region of S1 from SARS-CoV-2. Mo-CBP3-PepII and PepKAA had the highest affinity with it among all the therapeutic peptides analyzed. As a result of binding, both peptides caused conformational changes in the S protein, resulting in an inconsistent interaction with ACE2.[18] Peptide templates 1 and 2 have binding affinity values of -19 and -36 kcal/mol (ΔG MM/GBSA) for the S protein RBD, respectively. Adaptive mutations in templates 1, and 2, however, improve (ΔG MM/GBSA) by −24 and −45 kcal/mol, respectively.[20] MD simulations of azurin and its derivatives revealed that among them, P28 showed excellent binding affinity toward the ACE2 receptor.[21] A new hybrid peptide was created by joining two discontinuous peptide fragments from human ACE2 (hACE2) with a linker glycine (denoted as 22-44G351-357), and it was used as a basis for making new sequences with improved SARS-CoV-2 RBD-binding affinities. It shows a strong EvoEF2-binding score of −53.35 EEU (EvoEF2 energy unit) in comparison to wild type −46.46 EEU.[7]{Table 2}

The peptide as a therapeutic agent for SARS-CoV-2 in vitro and in vivo platforms

Following the in silico evaluation of binding affinity via negative binding free energy calculations, an in vitro platform assessment is required. Three studies have proven promising inhibitory effects against virulent SARS-CoV2 listed in [Table 3]. Several targets have been investigated to prevent virus infection or to limit virus entry into recipient cells. Victor et al. designed a lipopeptide that inhibits the formation of HR complexes with spike protein fusion at IC50 of 10 nM and IC90 of 100 nM.[27] However, they also evaluated the ex vivo platform to assess the preventive measure, and cytotoxicity toward overexpressing hACE2 and HEK293T or Vero cells by MTT assay, which shows nonsignificant toxicity at higher dose tested. According to Francesca Curreli et al. synthesized helical complementary to helix-1 of ACE2 named NYBSP-1 showed a promising effect by overexpression of ACE2 in HT1080/ACE2 cell lines and human lung cell lines A549/ACE2, using a pseudovirus-based single-cycle assay. IC50 was reported for HT1080/ACE2 ([IC50]: 1.9–4.1 μM) and A549/ACE2 (IC50: 2.2–2.8 μM) cells. The cytopathic effect also evaluated for NYBSP-1 showing efficient effect IC100 at 17.2 μM, other combination for stapled peptides shows IC100 at a higher concentration than NYBSP-2 and NYBSP-4 at 33 μM concentration.[25]{Table 3}

Another study by Maas et al. targeted RBD of spike protein toward hACE2, designed stapled peptide named A36K-F40E has potent inhibitory activity with (IC50: 3.6 μM, Kd: 2.1 μM) in RBD-hACE2-binding assay.[26]

Total of 4 peptides showed promising prophylactic effects in survival analysis in different animal models listed in [Table 4]. EK1 shows 100% prophylactic and 80% therapeutic efficacy in the pseudovirus infection mouse model. It is unclear whether the therapeutic efficacy of other modified EK1C4 lipo-peptides varies between 15-100%, while exhibiting similar prophylactic potential. However, IPB02 and SBP1 inhibit the fusion interaction with spike protein and RBD, respectively, showing the efficacious mechanism of action in the in vitro platform.{Table 4}

Therapeutic peptides in the clinical platform

There are few clinical trials that are under progress in evaluating the role of the peptide as a drug candidate in patients with SARS-CoV2 which are registered in the clinical trial registry. Peptides need to be thoroughly evaluated for safety and efficacy in all three platforms in silico, in vitro, and in vivo before entering into the clinical trials. Some peptide compounds have already entered into the phase 2 study after the successful completion of phase 1 which are listed in [Table 5].[27] The major outcomes that they have evaluated in these clinical trials include mortality rate, COVID-19 antigen test negative, the occurrence of any major adverse events, increase in antigen-specific antibody titer, and seroconversion rate.{Table 5}

Vaccine candidates

There are few studies that reported peptide-based vaccine design in in silico platforms toward different target-specific domains [Table 6]. Abdelmageed et al. reported envelope protein-binding affinity as a T-cell RBD, which shows well-predicted immunogenic effects.[11] Another few studies reported promising predicted immunogenic effects without showing auto-immunogenic effects; designs involved CD8+ T-cell, B-cell receptor/Fab molecular complexes, and T-cell RBD-based signaling.[11],[23],[29],[32] Multi-epitope-based peptide design is an effective approach toward SARS-CoV-19, and promising immunogenicity can be achieved, but auto-immunogenicity might be a major concern.[31] All the results reported by studies are predicted not actual, so in vivo studies are required to validate the above results.{Table 6}


Ease of synthesis and designing of peptides toward specific targets outperforms other drug development process strategies, which has recently been trending in special cases of druggable targets with a lower prevalence of adverse events. Three peptides or peptide mimetics have received Food and Drug Administration approval for different indications in the last 2 years, which explains their success story.[28]

Druggable targets for SARS-CoV-19 have been identified, which has aided in the design and development of various peptide-based therapeutics for this COVID-19 pandemic era, as well as clinical trials. The lack of appropriate in vivo evaluation techniques, on the other hand, is a major impediment to the collection of preclinical evidence on efficacy and toxicity. Although each approach has significant limitations, peptide-based therapeutics appear to be superior in all aspects except drug delivery and stability of active conformation.

In this concise review, we assessed the role of peptides or peptidomimetics as a therapeutic and preventive candidate for COVID-19 using various platforms, including in silico, in vitro, in vivo (preclinical animal models), and clinical trials. The majority of studies have focused on the interaction between the host ACE2 receptor and the spike (S) protein of SARS-CoV-2, which has been primarily targeted as peptides and peptide-based therapeutics. Peptides inhibited the receptor-binding domain of S protein in ACE2 receptors.

We discussed current trends in peptide-based therapeutic approaches used in the development of COVID-19 management in this brief review. Recent studies have provoked interest in the potential and success stories of peptide-based therapeutic approaches with limited time and resource field.[33]


In this brief review, we have critically evaluated the role of peptide and peptidomimetics in SARS-CoV-2 disease in the platforms of in silico, in vitro, in vivo (preclinical studies), and clinical trial. All are naming compounds. Expansion not available and not applicable. Ease of synthesis and design makes it a more accessible and thrust area of research.

Author contributions

Data conceived and retrieval and data extraction were done by JK. JK HS and SK wrote the manuscript, with AP's final approval. AP contributed to the critical revision of the manuscript and approved the final edition. BM and AP were approached for additional corrections.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


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