we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds). Screening a subset of these in multiple viral assays identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 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.
In this study, we have identified 332 high-confidence SARS-CoV-2-human PPIs connected to multiple biological processes, including protein trafficking, translation, transcription and ubiquitination regulation. Against these targets we found 69 ligands, including FDA approved drugs, compounds in clinical trials, and preclinical compounds. Antiviral tests in two different laboratories reveal two broad sets of active drugs and compounds; those impinging on translation, and those modulating Sigma1 and Sigma2 receptors. Within these sets are at least five targets and over ten different chemotypes, suggesting a rich landscape for optimization.In this study, we have identified 332 high-confidence SARS-CoV-2-human PPIs connected to multiple biological processes, including protein trafficking, translation, transcription and ubiquitination regulation. Against these targets we found 69 ligands, including FDA approved drugs, compounds in clinical trials, and preclinical compounds. Antiviral tests in two different laboratories reveal two broad sets of active drugs and compounds; those impinging on translation, and those modulating Sigma1 and Sigma2 receptors. Within these sets are at least five targets and over ten different chemotypes, suggesting a rich landscape for optimization.
Our approach of host-directed intervention as an antiviral strategy overcomes problems associated with drug resistance and may also provide pan-viral therapies as we prepare for the next pandemic. Furthermore, the possibilities for co-therapies are expanded, for example with drugs directly targeting the virus, including remdesivir, and, as we demonstrate in this study, a rich set of repurposing opportunities are illuminated. More broadly, the pipeline described here represents a new approach for drug discovery not only for pan-viral strategies, but for many diseases, and illustrates the speed in which science can be moved forward using a multi-disciplinary and collaborative approach.
Reference & source information: https://www.nature.com/
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