Potential Chimeric Peptides to Block the SARS-CoV-2 Spike RBD

Abstract

Background: There are no known medicines or vaccines to control the COVID-19 pandemic caused by SARS-CoV-2 (nCoV). Antiviral peptides are superior to conventional drugs and may also be effective against COVID-19. Hence, we investigated the SARS-CoV-2 Spike RBD (nCoV-RBD) that interacts with hACE2 for viral attachment and entry. Methods: Three strategies and bioinformatics approaches were employed to design potential nCoV-RBD - hACE2 interaction-blocking peptides that may restrict viral attachment and entry. Firstly, the key residues interacting with nCoV-RBD - hACE2 are identified and hACE2 sequence based peptides are designed. Second, peptides from five antibacterial peptide databases that block nCoV-RBD are identified; finally, a chimeric peptide design approach is used to design peptides that can bind to key nCoV-RBD residues. The final peptides are selected based on their physiochemical properties, numbers and positions of key residues binding, binding energy, and antiviral properties. Results: We found (i) three amino acid stretches in hACE2 interact with nCoV-RBD; (ii) effective peptides must bind to three key positions of nCoV-RBD: Gly485/Phe486/Asn487, Gln493, and Gln498/Thr500/Asn501; (iii) Phe486, Gln493, and Asn501 are critical residues; (iv) AC20 and AC23 derived from hACE2 may block two key critical positions; (iv) DBP6 identified from databases can block the three sites of the nCoV-RBD interacting with one critical position Gln498; (v) seven chimeric peptides were considered promising among which cnCoVP-3, cnCoVP-4, and cnCoVP-7 are the top three; and (vi) cnCoVP-4 meets all the criteria and is the best peptide. Conclusion: All the ten peptides need experimental validation for their therapeutic efficacy.

Potential chimeric peptides to block the SARS-CoV-2 spike receptor-binding domain

“…A 26 amino acid peptide (AC26) binds to Thr500 and Asn501 of the Spike RBD ( Figure 1A ), a 23 amino acid peptide (AC23) binds to Tyr489 and Thr500 of the Spike RBD ( Figure 1B ), and a third 20 amino acid peptide (AC20) binds to Gln493 and Asn501 of the Spike RBD ( Figure 1C ). All these peptides show acceptable physiochemical properties to be used as therapeutic peptides (see Extended data 26 ). However, none of these three peptides are able to block all the key three positions of the Spike RBD.…”

“…In our peptide database analysis, we also observed that the peptides that have been experimentally proven to be effective against SARS-CoV have the potential of being used against the SARS-CoV-2 Spike protein. All of the seven identified peptides (see Extended data 26 ) are of 20 amino acids in length and are reported to target the Spike protein of SARS-CoV to exhibit their anti-SARS virus activities 19 . Although the peptides show four to 11 “H” bonds and form between two to four bonds with our eight given target residues, most of these peptides do not bind to all the three positions ((i) Gly485 or Phe486 or Asn487, (ii) Gln493, and (iii) Gln498 or Thr500 or Asn501) to effectively block the Spike RBD.…”

“…The DBP1, DBP2, and DBP3 peptides bind to only the third position (Gln498 and Asn501) of the Spike RBD without binding to the other two sites ( Figure 2A–C ; Extended data 26 ). DBP4, DBP5, and DBP7 interact with the first (Gly485 or Phe486 or Asn487) and third (Gln498 and Asn501) sites of the Spike RBD without binding to the middle or the second site (Gln493) ( Figure 2D, E, G ; Extended data 26 ). DBP6 binds to all the three sites within the range of the target residues but does not interact with the key residues of the first and third sites ( Figure 2F ; Extended data 26 ).…”

“…ToxinPred 25 , with default parameters, was used to predict the toxicity (toxic or non-toxic) of the peptides. The final peptides were selected based on their: HPEPDOCK docking energy score (cut-off -120 or less), number of H bonds (>2), number of selected target residue bonds (2-10), number of key target residue bonds (>2), physiochemical properties (parameters acceptable for AMPs, see Extended data 26 ), and AVPpred prediction (Yes) 13 .…”

Evidence Supporting the Use of Peptides and Peptidomimetics As Potential SARS-CoV-2 (COVID-19) Therapeutics

“…Proposed in the report, at least one peptide inhibitor was able to specifically bind to the spike protein and prevent SARS-CoV-2–RBD/ACE2 interactions. Barh et al [ 47 ] and Huang et al [ 48 ] also shared their initial computational findings in preprints posted on preprints and BioRxiv , respectively. Using bioinformatics strategies, Barh et al screened and designed several potential anti-S protein peptides that may limit viral attachment and entry.…”