Computational design of ultrashort peptide inhibitors of the receptor-binding domain of the SARS-CoV-2 S protein

Abstract

Targeting the interaction between severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2)-receptor-binding domain (RBD) and angiotensin-converting enzyme 2 (ACE2) is believed to be an effective strategy for drug design to inhibit the infection of SARS-CoV-2. Herein, several ultrashort peptidase inhibitors against the RBD–ACE2 interaction were obtained by a computer-aided approach based on the RBD-binding residues on the protease domain (PD) of ACE2. The designed peptides were tested on a model coronavirus GX_P2V, which has 92.2 and 86% amino acid identity to the SARS-CoV-2 spike protein and RBD, respectively. Molecular dynamics simulations and binding free energy analysis predicted a potential binding pocket on the RBD of the spike protein, and this was confirmed by the specifically designed peptides SI5α and SI5α-b. They have only seven residues, showing potent antiviral activity and low cytotoxicity. Enzyme-linked immunosorbent assay result also confirmed their inhibitory ability against the RBD–ACE2 interaction. The ultrashort peptides are promising precursor molecules for the drug development of Corona Virus Disease 2019, and the novel binding pocket on the RBD may be helpful for the design of RBD inhibitors or antibodies against SARS-CoV-2.

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

“…Several studies introduced peptide inhibitors against RBD. However, they used different approaches to design peptides [ [54] , [55] , [56] , [57] , [58] , [59] , [60] ], and therefore, their results may seem incomparable to the present study. In the next step, 11 peptides having the greatest OSPREY scores were chosen and their probable allergenicity and toxicity were evaluated.…”

SARS-CoV-2 pan-variant inhibitory peptides deter S1-ACE2 interaction and neutralize delta and omicron pseudoviruses

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Bovine lactoferrin inhibits SARS‐CoV‐2 and SARS‐CoV‐1 by targeting the RdRp complex and alleviates viral infection in the hamster model

“… 12 It has been successfully demonstrated as a surrogate model for drug research on SARS‐CoV‐2. 4 , 13 , 14 In addition, transcription‐ and replication‐competent SARS‐CoV‐2 virus‐like particles (SARS‐CoV‐2 trVLPs) and SARS‐CoV‐2 pseudovirus are ideal alternative tools for studying antiviral drugs against SARS‐CoV‐2. 15 , 16 …”