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Abstract: During the current COVID-19 pandemic more than 160,000 people have died worldwide as of mid-April 2020, and the global economy has been crippled Effective control of the SARS-CoV2 virus that causes the COVID-19 pandemic requires both vaccines and antivirals Antivirals are particularly crucial to treat infected people during the period of time that an effective vaccine is being developed and deployed Because the development of specific antiviral drugs can take a considerable length of time, an important approach is to identify existing drugs already approved for use in humans which could be repurposed as COVID-19 therapeutics Here we focus on antivirals directed against the SARS-CoV2 M supro /suprotease, which is required for virus replication A structural similarity search showed that the Hepatitis C virus (HCV) NS3/4A protease has a striking three-dimensional structural similarity to the SARS-CoV2 M supro /suprotease, particularly in the arrangement of key active site residues We used virtual docking predictions to assess the hypothesis that existing drugs already approved for human use or clinical testing that are directed at the HCV NS3/4A protease might fit well into the active-site cleft of the SARS-CoV2 protease (M supro /su) AutoDock docking scores for 12 HCV protease inhibitors and 9 HIV-1 protease inhibitors were determined and compared to the docking scores for an alpha-ketoamide inhibitor of M supro /su, which has recently been shown to inhibit SARS-CoV2 virus replication in cell culture We identified eight HCV protease inhibitors that bound to the M supro /suactive site with higher docking scores than the alpha-ketoamide inhibitor, suggesting that these protease inhibitors may effectively bind to the M supro /suactive site These results provide the rationale for us to test the identified HCV protease inhibitors as inhibitors of the SARS-CoV2 protease, and as inhibitors of SARS-CoV2 virus replication Subsequently these repurposed drugs could be evaluated as COVID-19 therapeutics
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Structural Similarity of SARS-CoV2 Mpro and HCV NS3/4A Proteases Suggests New Approaches for Identifying Existing Drugs Useful as COVID-19 Therapeutics
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