Journal Article

Postinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection

Lovell, Scott, Kashipathy, Maithri M., Perlman, Stanley, Groutas, William C., Wong, Lok-Yin Roy, Dampalla, Chamandi S., Zheng, Jian, Battaile, Kevin P., Perera, Krishani Dinali, Kim, Yunjeong, Meyerholz, David K., Chang, Kyeong-Ok, Nguyen, Harry Nhat

2021

نظرة عامة

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.

• الناشر: National Academy of Sciences
• موضوع: Angiotensin-Converting Enzyme 2 - genetics / Animal models / Animals / antiviral / Antiviral agents / Antiviral Agents - chemical synthesis / Antiviral Agents - chemistry / Antiviral Agents - pharmacology / Antiviral Agents - therapeutic use / BASIC BIOLOGICAL SCIENCES / Biological Sciences / Cell culture / Coronavirus 3C Proteases - antagonists & inhibitors / Coronavirus 3C Proteases - chemistry / Coronavirus Papain-Like Proteases - antagonists & inhibitors / Coronavirus Papain-Like Proteases - chemistry / Coronaviruses / COVID-19 / COVID-19 - drug therapy / COVID-19 - pathology / Crystallography / Crystallography, X-Ray / Deuteration / Deuterium / Disease Models, Animal / Drug Evaluation, Preclinical / Female / Health risks / Infections / K18-ACE2 mice / Lung - pathology / Mice / Mice, Transgenic / Microbiology / Model testing / Models, Molecular / Molecular Structure / Protease / Protease inhibitors / Protease Inhibitors - chemical synthesis / Protease Inhibitors - chemistry / Protease Inhibitors - pharmacology / Protease Inhibitors - therapeutic use / Protein Conformation / Proteinase inhibitors / Public health / Pyrrolidines - chemistry / Pyrrolidines - therapeutic use / Replication / Respiratory diseases / SARS-CoV-2 / SARS-CoV-2 - drug effects / SARS-CoV-2 - enzymology / Severe acute respiratory syndrome coronavirus 2 / Sulfonic Acids / Survival / Transgenes / Viral diseases / Viruses