Large scale discovery of coronavirus-host factor protein interaction motifs reveals SARS-CoV-2 specific mechanisms and vulnerabilities

Many interactions between viral and host proteins are mediated by short peptide motifs. Here, using a phage-based viral peptide library, the authors identify 269 peptide-based interactions for 18 coronaviruses, including an interaction between SARS-CoV-2 N and G3BP1/2 that affects stress granules. Viral proteins make extensive use of short peptide interaction motifs to hijack cellular host factors. However, most current large-scale methods do not identify this important class of protein-protein interactions. Uncovering peptide mediated interactions provides both a molecular understanding of viral interactions with their host and the foundation for developing novel antiviral reagents. Here we describe a viral peptide discovery approach covering 23 coronavirus strains that provides high resolution information on direct virus-host interactions. We identify 269 peptide-based interactions for 18 coronaviruses including a specific interaction between the human G3BP1/2 proteins and an phi xFG peptide motif in the SARS-CoV-2 nucleocapsid (N) protein. This interaction supports viral replication and through its phi xFG motif N rewires the G3BP1/2 interactome to disrupt stress granules. A peptide-based inhibitor disrupting the G3BP1/2-N interaction dampened SARS-CoV-2 infection showing that our results can be directly translated into novel specific antiviral reagents.

Automated summary

The study identified 269 peptide-based interactions for 18 coronaviruses, highlighting the importance of short peptide interaction motifs in viral hijacking of host proteins. The specific interaction between SARS-CoV-2 N protein and human G3BP1/2 proteins was found to disrupt stress granules, with implications for the development of novel antiviral reagents. The results demonstrate the potential of peptide inhibitors to specifically target viral-host interactions for combating SARS-CoV-2 infection.