biostudies-literatureDampalla CSNIDDK NIH HHSNIAID NIH HHSHHS | NIH | National Institute of Allergy and Infectious DiseasesNIGMS NIH HHSe2101555118https://www.ebi.ac.uk/biostudies/studies/S-EPMC8307543biostudies-literatureUnknown118(29)Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to be a serious global public health threat. The 3C-like protease (3CLpro) is a virus protease encoded by SARS-CoV-2, which is essential for virus replication. We have previously reported a series of small-molecule 3CLpro inhibitors effective for inhibiting replication of human coronaviruses including SARS-CoV-2 in cell culture and in animal models. Here we generated a series of deuterated variants of a 3CLpro inhibitor, GC376, and evaluated the antiviral effect against SARS-CoV-2. The deuterated GC376 displayed potent inhibitory activity against SARS-CoV-2 in the enzyme- and the cell-based assays. The K18-hACE2 mice develop mild to lethal infection commensurate with SARS-CoV-2 challenge doses and were proposeProceedings of the National Academy of Sciences of the United States of AmericaPostinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection.PMC8307543R01 AI129269P30 DK054759R01 AI109039P30 GM133893T32 AI007511P01 AI060699Meyerholz DKPerlman SGroutas WCNguyen HNPerera KDLovell SDampalla CSWong LRZheng JKashipathy MMChang KOKim YBattaile KPfalsePostinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection.Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to be a serious global public health threat. The 3C-like protease (3CLpro) is a virus protease encoded by SARS-CoV-2, which is essential for virus replication. We have previously reported a series of small-molecule 3CLpro inhibitors effective for inhibiting replication of human coronaviruses including SARS-CoV-2 in cell culture and in animal models. Here we generated a series of deuterated variants of a 3CLpro inhibitor, GC376, and evaluated the antiviral effect against SARS-CoV-2. The deuterated GC376 displayed potent inhibitory activity against SARS-CoV-2 in the enzyme- and the cell-based assays. The K18-hACE2 mice develop mild to lethal infection commensurate with SARS-CoV-2 challenge doses and were propose2021-01-01T00:00:00Z2021 Jul2026-05-08T05:35:12.904Z2022-02-11T00:13:33.22ZS-EPMC83075433421073810.1073/pnas.2101555118