A SARS-CoV-2 Protein Interaction Map Reveals Targets for Drug-Repurposing

By D. Gordon, Gwendolyn M. Jang, Mehdi Bouhaddou, Jiewei Xu, K. Obernier, K. White, Matthew J. O’Meara, V. Rezelj, Jeffrey Z. Guo, D. Swaney and 115 more. 2020

3,895 citations recorded by the source corpus.

A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption1,2. There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein–protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors. Further studies of these host-factor-targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19. A human–SARS-CoV-2 protein interaction map highlights cellular processes that are hijacked by the virus and that can be targeted by existing drugs, including inhibitors of mRNA translation and predicted regulators of the sigma receptors.

Subfields: Computational Theory and Mathematics, Infectious Diseases, Molecular Biology

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Citations in the corpus

Emergence of genomic diversity and recurrent mutations in SARS-CoV-2 (2020, positive): “Extensive genomic resources for SARS-CoV-1 should in principle also be key to informing on optimal drug and vaccine design, particularly when coupled with knowledge of human proteome and immune interactions (29).”
Sarbecovirus ORF6 proteins hamper induction of interferon signaling (2021, methodology): “, 2020) and selinexor (Gordon et al., 2020) may be candidates for treatment of COVID-19 as they target the activity of ORF6.”
Structure of SARS-CoV-2 ORF8, a rapidly evolving immune evasion protein (2020, background): “Many putative cellular interactors have been identified (13, 20), but the mechanism of action of ORF8 with respect to these interactors is still unclear.”
Immunology of COVID-19: Current State of the Science (2020, positive): “Other proteins, including SARS-CoV-1 PLP, N, ORF3b, and ORF6, block IRF3 phosphorylation and nuclear translocation (Devaraj et al., 2007; Kopecky-Bromberg et al., 2007).”
SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling (2020, background): “Hence, despite having only 69% amino acid identity, SARS-CoV and SARS-CoV-2 Orf6 can both effectively antagonize IFN signaling.”
The BioGRID database: A comprehensive biomedical resource of curated protein, genetic, and chemical interactions (2020, background): “For example, interactions of the BRD2 chromatin reader with the SARS-CoV-2 Envelope (E) protein and ORF14 protein 30,31 are shown in the network view for BRD2 (Figure 2a).”
The reactome pathway knowledgebase 2022 (2021, positive): “We have assembled a catalog of drug molecules that could potentially be repurposed to treat COVID-19 (https:// reactome.org/content/detail/R-HSA-9679191, Figure 1), incorporating the extensive drug list assembled by Gordon et al. (14), and supplementing it with data from recent publications.”
Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity (2020, positive): “To understand the differences in the pathophysiological roles of SCoV2-PLpro and SCoV-PLpro, and to expand our knowledge of the SARS-CoV-2 protein interaction map 23 , we analysed the cellular inter-actome of both proteins.”
Cryo-EM structure of the SARS-CoV-2 3a ion channel in lipid nanodiscs (2020, background): “72 e- Å2 in the first set (1-2007) and second set (2008-6309) of movies respectively.”