Repurposing the HCV NS3–4A protease drug boceprevir as COVID-19 therapeutics
Rick Oerlemans, Angel J. Ruiz‐Moreno, Yingying Cong, Nilima Dinesh Kumar, Marco A. Velasco‐Velázquez, Constantinos G. Neochoritis, Jolanda Smith, Fulvio Reggiori, Matthew R. Groves, Alexander Dömlingꝉ
Abstract
drug discovery takes years to move from idea and/or pre-clinic to market, and it is not a short-term solution for the current SARS-CoV-2 pandemic. Drug repurposing is perhaps the only short-term solution, while vaccination is a middle-term solution. Here, we describe the discovery path of the HCV NS3-4A protease inhibitors boceprevir and telaprevir as SARS-CoV-2 main protease (3CLpro) inhibitors. Based on our hypothesis that α-ketoamide drugs can covalently bind to the active site cysteine of the SARS-CoV-2 3CLpro, we performed docking studies, enzyme inhibition and co-crystal structure analyses and finally established that boceprevir, but not telaprevir, inhibits replication of SARS-CoV-2 and mouse hepatitis virus (MHV), another coronavirus, in cell culture. Based on our studies, the HCV drug boceprevir deserves further attention as a repurposed drug for COVID-19 and potentially other coronaviral infections as well.