6ZRT

Crystal structure of SARS CoV2 main protease in complex with inhibitor Telaprevir

Summary for 6ZRT

• Entry DOI: 10.2210/pdb6zrt/pdb
• Descriptor: Main Protease, DIMETHYL SULFOXIDE, (1S,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-N-[(2R,3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl]octahydrocyclopenta[c]pyrrole-1-carboxamide, ... (4 entities in total)
• Functional Keywords: protease, telaprevir, inhibitor, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 34585.54

Authors

Oerlemans, R.,Wang, W.,Lunev, S.,Domling, A.,Groves, M.R. (deposition date: 2020-07-14, release date: 2020-08-12, Last modification date: 2024-11-06)

Primary citation

Oerlemans, R.,Ruiz-Moreno, A.J.,Cong, Y.,Dinesh Kumar, N.,Velasco-Velazquez, M.A.,Neochoritis, C.G.,Smith, J.,Reggiori, F.,Groves, M.R.,Domling, A.
Repurposing the HCV NS3-4A protease drug boceprevir as COVID-19 therapeutics.
Rsc Med Chem, 12:370-379, 2020

PubMed Abstract: The rapid growth of COVID-19 cases is causing an increasing death toll and also paralyzing the world economy. 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.

PubMed: 34041486
DOI: 10.1039/d0md00367k

Experimental method

X-RAY DIFFRACTION (2.1 Å)