Abstract
The COVID-19 pandemic caused by SARS-CoV-2 requires rapid development of specific therapeutics and vaccines. The main protease of SARS-CoV-2, 3CL M pro , 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 M pro . 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.
Keywords: 3CL M(pro); 3CL main protease; SARS-CoV-2; drug design; enzyme kinetics; hepatitis C clinical drugs; protease inhibitor; repurposing clinical drugs; room temperature X-ray crystallography.
【저자키워드】 SARS-CoV-2, drug design, 3CL main protease, Protease inhibitor, 3CL M(pro), enzyme kinetics, hepatitis C clinical drugs, repurposing clinical drugs, room temperature X-ray crystallography., 【초록키워드】 Vaccines, drug design, COVID-19 pandemic, Crystallography, repurposing, X-ray crystallography, drug, protease, in vitro, inhibitors, protease inhibitors, COVID-19 treatments, binding affinity, COVID-19 treatment, Protease inhibitor, Hepatitis, hepatitis C, drug target, virus replication, temperature, inhibitor, 3CL, binding, boceprevir, narlaprevir, telaprevir, room temperature, (telaprevir, enzyme, M pro, leupeptin, offer, aldehyde, malleability, caused, faster, reveal, the binding affinity, inhibit SARS-CoV-2, 【제목키워드】 Cavity, clinical, 3CL, M pro, the SARS-CoV-2,