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Inhibition of SARS-CoV-2 pathogenesis by potent peptides designed by the mutation of ACE2 binding region.

ABSTRACT: The outbreak of COVID-19 has resulted in millions of deaths. Despite all attempts that have been made to combat the pandemic, the re-emergence of new variants complicated SARS-CoV-2 eradication. The ongoing global spread of COVID-19 demands the incessant development of novel agents in vaccination, diagnosis, and therapeutics. Targeting receptor-binding domain (RBD) of spike protein by which the virus identifies host receptor, angiotensin-converting enzyme (ACE2), is a promising strategy for curbing viral infection. This study aims to discover novel peptide inhibitors against SARS-CoV-2 entry using computational approaches. The RBD binding domain of ACE2 was extracted and docked against the RBD. MMPBSA calculations revealed the binding energies of each residue in the template. The residues with unfavorable binding energies were considered as mutation spots by OSPREY. Binding energies of the residues in RBD-ACE2 interface was determined by molecular docking. Peptide inhibitors were designed by the mutation of RBD residues in the virus-receptors complex which had unfavorable energies. Peptide tendency for RBD binding, safety, and allergenicity were the criteria based on which the final hits were screened among the initial library. Molecular dynamics simulations also provided information on the mechanisms of inhibitory action in peptides. The results were finally validated by molecular docking simulations to make sure the peptides are capable of hindering virus-host interaction. Our results introduce three peptides P7 (RAWTFLDKFNHEAEDLRYQSSLASWN), P13 (RASTFLDKFNHEAEDLRYQSSLASWN), and P19 (RADTFLDKFNHEAEDLRYQSSLASWN) as potential effective inhibitors of SARS-CoV-2 entry which could be considered in drug development for COVID-19 treatment.

SUBMITTER: Pourmand S

PROVIDER: S-EPMC9110306 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Angiotensin-converting enzyme 2 (ACE2) is the host cellular receptor that locks onto the surface spike protein of the 2002 SARS coronavirus (SARS-CoV-1) and of the novel, highly transmissible and deadly 2019 SARS-CoV-2, responsible for the COVID-19 pandemic. One strategy to avoid the virus infection is to design peptides by extracting the human ACE2 peptidase domain α1-helix, which would bind to the coronavirus surface protein, preventing the virus entry into the host cells. The natural α1-helix peptide has a stronger affinity to SARS-CoV-2 than to SARS-CoV-1. Another peptide was designed by joining α1 with the second portion of ACE2 that is far in the peptidase sequence yet grafted in the spike protein interface with ACE2. Previous studies have shown that, among several α1-based peptides, the hybrid peptidic scaffold is the one with the highest/strongest affinity for SARS-CoV-1, which is comparable to the full-length ACE2 affinity. In this work, binding and folding dynamics of the natural and designed ACE2-based peptides were simulated by the well-known coarse-grained structure-based model, with the computed thermodynamic quantities correlating with the experimental binding affinity data. Furthermore, theoretical kinetic analysis of native contact formation revealed the distinction between these processes in the presence of the different binding partners SARS-CoV-1 and SARS-CoV-2 spike domains. Additionally, our results indicate the existence of a two-state folding mechanism for the designed peptide en route to bind to the spike proteins, in contrast to a downhill mechanism for the natural α1-helix peptides. The presented low-cost simulation protocol demonstrated its efficiency in evaluating binding affinities and identifying the mechanisms involved in the neutralization of spike-ACE2 interaction by designed peptides. Finally, the protocol can be used as a computer-based screening of more potent designed peptides by experimentalists searching for new therapeutics against COVID-19.

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Inhibition of SARS-CoV-2 pathogenesis by potent peptides designed by the mutation of ACE2 binding region.

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