Kruse T, Benz C, Garvanska DH, Lindqvist R, Mihalic F, Coscia F, Inturi R, Sayadi A, Simonetti L, Nilsson E, Ali M, Kliche J, Moliner Morro A, Mund A, Andersson E, McInerney G, Mann M, Jemth P, Davey NE, Överby AK, Nilsson J, Ivarsson Y
Nat Commun 12 (1) 6761 [2021-11-19; online 2021-11-19]
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 ΦxFG peptide motif in the SARS-CoV-2 nucleocapsid (N) protein. This interaction supports viral replication and through its ΦxFG 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.