biostudies-literatureZhou YNCATS NIH HHSNIA NIH HHSNIDDK NIH HHSNHLBI NIH HHSNHGRI NIH HHSNLM NIH HHSU.S. Department of Health & Human Services | National Institutes of HealthNIGMS NIH HHS128-139https://www.ebi.ac.uk/biostudies/studies/S-EPMC9851973biostudies-literatureUnknown41(1)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.Nature biotechnologyA comprehensive SARS-CoV-2-human protein-protein interactome reveals COVID-19 pathobiology and potential host therapeutic targets.PMC9851973R01 DK115398R01 GM130885F31 HG010820R01 LM013337UM1 HG009393UL1 TR001422R01 AG066707R01 AG076448RM1GM139738U01 HG009391R01 HL060917R56 AG074001R35 GM122550U01 AG073323R37 HL060917RM1 GM139738R01 GM125639R01GM124559R01 GM124559Gula HGupta SCheng FWierbowski SNerkar MNicolaescu VZhou YHou YBertolotti MFeschotte CParamo MIJehi LYu HLiu YTay SJudd JWang PMao CErzurum SCLis JTLuo YDrayman NRandall GfalseA comprehensive SARS-CoV-2-human protein-protein interactome reveals COVID-19 pathobiology and potential host therapeutic targets.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.2023-01-01T00:00:00Z2023 Jan2026-05-28T16:46:17.243Z2025-02-19T03:00:29.953ZS-EPMC98519733621703010.1038/s41587-022-01474-0