Computational design of peptide inhibitors targeting the interaction of ACE۲ and the spike receptor-binding domain of the SARS-CoV-۲ Omicron variant

The severe acute respiratory syndrome coronavirus ۲ (SARS-CoV-۲) is the seventh human coronavirus thatcauses the coronavirus disease (COVID-۱۹) after attacking the upper respiratory system and may lead torespiratory, enteric, hepatic, and neurologic diseases. Omicron variant (B.۱.۱.۵۲۹) is a recent SARS-CoV-۲variant of concern (VOC) with a large number of mutations in spike protein and with impacts on viraltransmissibility, disease severity, and efficacy of vaccines and therapeutics. Here, we designed a set ofpeptide inhibitors to block the protein–protein interactions (PPIs) of the receptor binding domain (RBD) ofthe SARS-CoV-۲ Omicron variant with human ACE۲ using computational methods. Based on the keyinteracting residues involved in the interaction site of RBD and ACE۲ that were analyzed by hotspotprediction tools, PIC and Ligplot+, a set of inhibitory peptides was designed. CABS-dock was used formolecular docking of designed peptides with spike protein of Omicron variant. Prodigy and HawkDockwebservers predicted the binding affinity of peptide-protein complexes and MM/GBSA free energydecompositions. Drug-likeness and ADME-Tox analysis were done by SwissADME and FAF-drugs۴ tocompute the physicochemical descriptors and properties of the designed peptides. Peptides are lessimmunogenic than recombinant proteins or monoclonal antibodies, with higher solubility and betterbiological efficiency than therapeutic proteins. Antibodies cannot penetrate to the cell membrane to targetintracellular PPIs and small molecules are not promising candidates for targeting challenging desired largeand flat PPIs binding sites. The designed interfering peptides with the most negative binding energies, theproper binding sites, and the acceptable properties are the potential candidates to develop as novelanticoronaviral therapeutics for COVID-۱۹ or future related CoV’s outbreaks.

کلیدواژه ها:

SARS-CoV-۲ ، Protein-protein interactions ، Inhibitory peptide ، Omicron variant ، Receptorbinding domain