Postinfection 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 proposed as a model for efficacy testing of antiviral agents. We treated lethally infected mice with a deuterated derivative of GC376. Treatment of K18-hACE2 mice at 24 h postinfection with a derivative (compound 2) resulted in increased survival of mice compared to vehicle-treated mice. Lung virus titers were decreased, and histopathological changes were ameliorated in compound 2-treated mice compared to vehicle-treated mice. Structural investigation using high-resolution crystallography illuminated binding interactions of 3CLpro of SARS-CoV-2 and SARS-CoV with deuterated variants of GC376. Taken together, deuterated GC376 variants have excellent potential as antiviral agents against SARS-CoV-2.
Mesh Terms:
Angiotensin-Converting Enzyme 2, Animals, Antiviral Agents, COVID-19, COVID-19 Drug Treatment, Coronavirus 3C Proteases, Coronavirus Papain-Like Proteases, Crystallography, X-Ray, Deuterium, Disease Models, Animal, Drug Evaluation, Preclinical, Female, Lung, Mice, Mice, Transgenic, Models, Molecular, Molecular Structure, Protease Inhibitors, Protein Conformation, Pyrrolidines, SARS-CoV-2, Sulfonic Acids, Transgenes
Angiotensin-Converting Enzyme 2, Animals, Antiviral Agents, COVID-19, COVID-19 Drug Treatment, Coronavirus 3C Proteases, Coronavirus Papain-Like Proteases, Crystallography, X-Ray, Deuterium, Disease Models, Animal, Drug Evaluation, Preclinical, Female, Lung, Mice, Mice, Transgenic, Models, Molecular, Molecular Structure, Protease Inhibitors, Protein Conformation, Pyrrolidines, SARS-CoV-2, Sulfonic Acids, Transgenes
Proc Natl Acad Sci U S A
Date: Jul. 20, 2021
PubMed ID: 34210738
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