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

Kruse, T.; Benz, C.; Garvanska, D. H.; 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. M.; Mann, M.; Jemth, P.; Davey, N. E.; Overby, A. K.; Nilsson, J.; Ivarsson, Y.

doi:10.1101/2021.04.19.440086

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bioRxiv · 10.1101/2021.04.19.440086

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

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Abstract

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 {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 blocks SARS-CoV-2 infection showing that our results can be directly translated into novel specific antiviral reagents.

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Kruse, T., Benz, C., Garvanska, D. H., 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. M., Mann, M., Jemth, P., Davey, N. E., Overby, A. K., Nilsson, J., Ivarsson, Y.. 2021-04-19. Large scale discovery of coronavirus-host factor protein interaction motifs reveals SARS-CoV-2 specific mechanisms and vulnerabilities. https://doi.org/10.1101/2021.04.19.440086

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