气候变化领域集成服务门户(CCPortal): Postinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection

CCPortal

DOI	10.1073/pnas.2101555118
	Postinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection
	Dampalla C.S.; Zheng J.; Perera K.D.; Wong L.-Y.R.; Meyerholz D.K.; Nguyen H.N.; Kashipathy M.M.; Battaile K.P.; Lovell S.; Kim Y.; Perlman S.; Groutas W.C.; Chang K.-O.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:29
英文摘要	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. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Antiviral; K18-ACE2 mice; Protease inhibitors; SARS-CoV-2
语种	英语
scopus关键词	ACE2 protein, human; antivirus agent; deuterium; GC376; proteinase inhibitor; pyrrolidine derivative; animal; chemical structure; chemistry; comparative study; disease model; drug effect; drug therapy; enzymology; female; genetics; lung; molecular model; mouse; pathology; preclinical study; protein conformation; synthesis; transgene; transgenic mouse; X ray crystallography; Angiotensin-Converting Enzyme 2; Animals; Antiviral Agents; Coronavirus 3C Proteases; Coronavirus Papain-Like Proteases; COVID-19; 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; Transgenes
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/238863
作者单位	Department of Chemistry, Wichita State University, Wichita, KS 67260, United States; Department of Microbiology and Immunology, University of Iowa, Iowa City, IA 52242, United States; Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, United States; Department of Pathology, University of Iowa, Iowa City, IA 52242, United States; Protein Structure Laboratory, University of Kansas, Lawrence, KS 66047, United States; NYX, New York Structural Biology Center, Upton, NY 11973, United States
推荐引用方式 GB/T 7714	Dampalla C.S.,Zheng J.,Perera K.D.,et al. Postinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection[J],2021,118(29).
APA	Dampalla C.S..,Zheng J..,Perera K.D..,Wong L.-Y.R..,Meyerholz D.K..,...&Chang K.-O..(2021).Postinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection.Proceedings of the National Academy of Sciences of the United States of America,118(29).
MLA	Dampalla C.S.,et al."Postinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection".Proceedings of the National Academy of Sciences of the United States of America 118.29(2021).