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A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing

An outbreak of the novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 290,000 people since the end of 2019, killed over 12,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven efficacy nor are there vaccines for its prevention. Unfortunately, the scientific community has little knowledge of the molecular details of SARS-CoV-2 infection. To illuminate this, we cloned, tagged and expressed 26 of the 29 viral proteins in human cells and identified the human proteins physically associated with each using affinitypurification mass spectrometry (AP-MS), which identified 332 high confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 67 druggable human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials and/or preclinical compounds, that we are currently evaluating for efficacy in live SARS-CoV-2 infection assays. The identification of host dependency factors mediating virus infection may provide key insights into effective molecular targets for developing broadly acting antiviral therapeutics against SARS-CoV-2 and other deadly coronavirus strains.

So far, no clinically available antiviral drugs have been developed for SARS-CoV, SARS-CoV-2 or MERS-CoV. Clinical trials are ongoing for treatment of COVID-19 with the nucleotide analog RNA-dependent RNA Polymerase (RdRP) inhibitor remdesivir9–11, and recent data suggests a new nucleotide analog may be effective against SARS-CoV-2 infection in laboratory animals12. Clinical trials on several vaccine candidates are also underway13, as well as trials of repurposed host-directed compounds inhibiting the human protease TMPRSS214. We believe there is great potential in systematically exploring the host dependencies of the SARS-CoV-2 virus to identify other host proteins already targeted with existing drugs. Therapies targeting the host-virus interface, where mutational resistance is arguably less likely, could potentially present durable, broad-spectrum treatment (which was not certified by peer review) is the author/funder. It is made available under a CC-BY 4.0 International license. bioRxiv preprint doi: https://doi.org/10.1101/2020.03.22.002386. this version posted March 23, 2020. The copyright holder for this preprint modalities15. Unfortunately, our minimal knowledge of the molecular details of SARS-CoV-2 infection precludes a comprehensive evaluation of small molecule candidates for host-directed therapies. We sought to address this knowledge gap by systematically mapping the interaction landscape between SARS-CoV-2 proteins and human proteins.

TThe SARS-CoV-2 interactome reveals novel aspects of SARS-CoV-2 biology that can be targeted pharmacologically. (a) Protein N targets stress granule proteins. (i) Protein N interactome. (ii) Model for therapeutic targeting of N interactions in the formation of stress granules (SGs). SGs are known to exhibit antiviral activity, with the integrative stress response (ISR) inducing eIF2α phosphorylation and SG formation, and Casein kinase II (CK2) disrupting and preventing the formation of SGs. By activating SG formation, or inhibiting CK2, the cellular environment could potentially shift to a more antiviral state.
 

期刊連結
https://www.biorxiv.org/content/10.1101/2020.03.22.002386v2