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The COVID-19 pandemic caused by SARS-CoV-2 requires rapid development of specific therapeutics and vaccines. SARS-CoV-2 main protease, 3CL Mpro, is an established drug target for the design of inhibitors to stop the virus replication. Repurposing existing clinical drugs can offer a faster route to treatments. Here, we report on the binding mode and inhibition properties of several inhibitors using room-temperature X-ray crystallography and in vitro enzyme kinetics. The enzyme active site cavity reveals a high degree of malleability, allowing aldehyde leupeptin and hepatitis C clinical protease inhibitors (telaprevir, narlaprevir, and boceprevir) to bind and inhibit SARS-CoV-2 3CL Mpro. Narlaprevir, boceprevir and telaprevir are low micromolar inhibitors, whereas the binding affinity of leupeptin is substantially weaker. Repurposing hepatitis C clinical drugs as COVID-19 treatments may be a useful option to pursue. The observed malleability of the enzyme active site cavity should be considered for the successful design of specific protease inhibitors.
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10.1016/j.str.2020.10.007
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document_parses/pdf_json/1d03f46014214821d48f88606193b84979d7043a.json
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Malleability of the SARS-CoV-2 3CL Mpro active site cavity facilitates binding of clinical antivirals
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