Multi-level proteomics reveals host-perturbation strategies of SARS-CoV-2 and SARS-CoV.

The sudden global emergence of SARS-CoV-2 urgently requires an in-depth understanding of molecular functions of viral proteins and their interactions with the host proteome. A number of -omics studies already significantly extended our knowledge of COVID-19 pathophysiology, including some focused on proteomics (refs Krogan, Christian Münch, Messner). To understand how SARS-CoV-2 and related coronaviruses manipulate the host, we need to identify the connections between such datasets, evaluate the functional effects of the individual viral proteins and put these findings into the context of host signalling pathways. Here we used the latest proteomics technology to quantitatively study the interactomes of closely related SARS-CoV-2 and SARS-CoV viruses as well as the influence of SARS-CoV-2 on transcriptome, proteome, ubiquitinome and phosphoproteome of a lung-derived human cell line. Projecting these data onto the global network of cellular interactions allowed us to discover relationships between the perturbations taking place upon SARS-CoV-2 infection at different layers and to identify unique and common molecular mechanisms of SARS coronaviruses. The results highlight the functionality of individual proteins as well as vulnerability hotspots of SARS-CoV-2, which can be targeted with clinically-approved drugs. We exemplify this by identification of kinase inhibitors as well as MMPase inhibitors with significant antiviral effects against SARS-CoV-2.