A comprehensive SARS-CoV-2–human protein–protein interactome reveals COVID-19 pathobiology and potential host therapeutic targets

• DOI: 10.1038/s41587-022-01474-0
• Publication Date: 2022-10-10T16:04:06Z
• Authors: Yadi Zhou; Yuan Liu; Shagun Gupta; Mauricio I. Paramo; Yuan Hou; Chengsheng Mao; Yuan Luo; Julius Judd; Shayne Wierbowski; Marta Bertolotti; Mriganka Nerkar; Lara Jehi; Nir Drayman; Vlad Nicolaescu; Haley Gula; Savaş Tay; Glenn Randall; Peihui Wang; John T. Lis; Cédric Feschotte; Serpil C. Erzurum; Feixiong Cheng; Haiyuan Yu
• Keywords: Viral Proteins; 0303 health sciences; 03 medical and health sciences; Gene Expression Regulation; SARS-CoV-2; Protein Interaction Mapping; Humans; COVID-19; Cell Line; 3. Good health

Studying viral-host protein-protein interactions can facilitate the discovery of therapies for viral infection. We use high-throughput yeast two-hybrid experiments and mass spectrometry to generate a comprehensive SARS-CoV-2-human protein-protein interactome network consisting of 739 high-confidence binary and co-complex interactions, validating 218 known SARS-CoV-2 host factors and revealing 361 novel ones. Our results show the highest overlap of interaction partners between published datasets and of genes differentially expressed in samples from COVID-19 patients. We identify an interaction between the viral protein ORF3a and the human transcription factor ZNF579, illustrating a direct viral impact on host transcription. We perform network-based screens of >2,900 FDA-approved or investigational drugs and identify 23 with significant network proximity to SARS-CoV-2 host factors. One of these drugs, carvedilol, shows clinical benefits for COVID-19 patients in an electronic health records analysis and antiviral properties in a human lung cell line infected with SARS-CoV-2. Our study demonstrates the value of network systems biology to understand human-virus interactions and provides hits for further research on COVID-19 therapeutics.