Abstract
The main protease (M pro , 3CL pro ) of SARS-CoV-2 is an attractive target in coronaviruses because of its crucial involvement in viral replication and transcription. Here, we report on the design, synthesis, and structure-activity relationships of novel small-molecule thioesters as SARS-CoV-2 M pro inhibitors. Compounds 3w and 3x exhibited excellent SARS-CoV-2 M pro inhibition with k inac / K i of 58,700 M -1 s -1 ( K i = 0.0141 μM) and 27,200 M -1 s -1 ( K i = 0.0332 μM), respectively. In Calu-3 and Vero76 cells, compounds 3h , 3i, 3l , 3r , 3v , 3w , and 3x displayed antiviral activity in the nanomolar range without host cell toxicity. Co-crystallization of 3w and 3af with SARS-CoV-2 M pro was accomplished, and the X-ray structures showed covalent binding with the catalytic Cys145 residue of the protease. The potent SARS-CoV-2 Mpro inhibitors also inhibited the M pro of other beta-coronaviruses, including SARS-CoV-1 and MERS-CoV, indicating that they might be useful to treat a broader range of coronaviral infections.
【초록키워드】 Structure, SARS-CoV-2, Transcription, Toxicity, 3CL pro, protease, antiviral activity, SARS-CoV-1, MERS-CoV, inhibitors, Replication, SARS-CoV-2 Mpro, X-ray, infections, cells, viral replication, inhibitor, synthesis, Calu-3, host cell, crystallization, residue, Compound, M pro, treat, Calu, Cys145, covalent binding, Coronaviral, inhibited, exhibited, coronavirus, in viral, catalytic, beta-coronaviruses, 【제목키워드】 Structure, SARS-CoV-2, inhibition, activity, X-ray, thioester, Determination,