Identification of motif-based interactions between SARS-CoV-2 protein domains and human peptide ligands pinpoint antiviral targets

Abstract

The virus life cycle depends on host-virus protein-protein interactions, which often involve a disordered protein region binding to a folded protein domain. Here, we used proteomic peptide phage display (ProP-PD) to identify peptides from the intrinsically disordered regions of the human proteome that bind to folded protein domains encoded by the SARS-CoV-2 genome. Eleven folded domains of SARS-CoV-2 proteins were found to bind 281 peptides from human proteins, and affinities of 31 interactions involving eight SARS-CoV-2 protein domains were determined (KD ∼ 7-300 μM). Key specificity residues of the peptides were established for six of the interactions. Two of the peptides, binding Nsp9 and Nsp16, respectively, inhibited viral replication. Our findings demonstrate how high-throughput peptide binding screens simultaneously identify potential host-virus interactions and peptides with antiviral properties. Furthermore, the high number of low-affinity interactions suggest that overexpression of viral proteins during infection may perturb multiple cellular pathways.

An association study of m6A methylation with major depressive disorder

“…It participates in biological pathways (go: 004482935): positive regulation of host involvement in viral genome replication [ 47 ]. Previous studies have found that YTHDC2 is involved in identifying the structure domains of SARS-CoV-2 proteins and the sequence-based interactions with human peptide ligands, accurately targeting antiviral sites [ 48 ]. Previous research has indicated that m6A plays a role in promoting and inhibiting inflammation in the brain [ 49 ].…”

A structural analysis of the nsp9 protein from the coronavirus MERS CoV reveals a conserved RNA binding interface

“…Interestingly, a recently published study 28 has identified peptides that significantly affect viral replication through the specific inhibition of the nsp9‐nsp12 interaction. Similar strategies to block either RNA binding or dimerization of nsp9 5 will aid in the process of developing new therapeutic strategies against SARS CoV‐2 or other newly emerging CoVs.…”

Exploring Viral–Host Protein Interactions as Antiviral Therapies: A Computational Perspective

“…These findings highlight the potential of high-throughput peptide binding screens in simultaneously revealing host–virus interactions and identifying peptides with antiviral properties. Additionally, the prevalence of low-affinity interactions suggests that overexpressing viral proteins during infection may disrupt multiple cellular pathways [ 51 ]. Similarly, in one study, researchers identified six host targets, including CARD9 and CYP51A1, associated with both fungal infections and SARS-CoV-2 interactions, suggesting them as potential antiviral therapeutics [ 52 ].…”