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

Kruse, Thomas; Benz, Caroline; Garvanska, Dimitriya H.; Lindqvist, Richard; Mihalic, Filip; Coscia, Fabian; Inturi, Ravi Teja; Sayadi, Ahmed; Simonetti, Leandro; Nilsson, Emma; Ali, Muhammad; Kliche, Johanna; Morro, Ainhoa Moliner; Mund, Andreas; Andersson, Eva; McInerney, Gerald; Mann, Matthias; Jemth, Per; Davey, Norman E; Överby, Anna K; Nilsson, Jakob; Ivarsson, Ylva

Viral proteins make extensive use of short peptide interaction motifs to hijack cellular host factors. However, current 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 scalable viral peptide discovery approach covering 229 RNA viruses 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 blocks SARS-CoV-2 infection showing that our results can be directly translated into novel specific antiviral reagents.