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

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

Proceedings of the National Academy of Sciences - PNAS, 2021-07, Vol.118 (29), p.1 [Periódico revisado por pares]

United States: National Academy of Sciences

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Título:
Postinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection
Autor: Dampalla, Chamandi S ; Zheng, Jian ; Perera, Krishani Dinali ; Wong, Lok-Yin Roy ; Meyerholz, David K ; Nguyen, Harry Nhat ; Kashipathy, Maithri M ; Battaile, Kevin P ; Lovell, Scott ; Kim, Yunjeong ; Perlman, Stanley ; Groutas, William C ; Chang, Kyeong-Ok
Assuntos: 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 - 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 ; 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 ; Severe acute respiratory syndrome coronavirus 2 ; Sulfonic Acids ; Survival ; Transgenes ; Viral diseases ; Viruses
É parte de: Proceedings of the National Academy of Sciences - PNAS, 2021-07, Vol.118 (29), p.1
Notas: AC02-06CH11357; SC0012704
USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division
Author contributions: Y.K., S.P., W.C.G., and K.-O.C. designed research; C.S.D., J.Z., K.D.P., L.-Y.R.W., H.N.N., M.M.K., S.L., and Y.K. performed research; D.K.M., K.P.B., S.L., Y.K., S.P., W.C.G., and K.-O.C. analyzed data; and S.L., Y.K., S.P., W.C.G., and K.-O.C. wrote the paper.
Edited by Michael B. A. Oldstone, Scripps Research Institute, La Jolla, CA, and approved May 11, 2021 (received for review January 25, 2021)
1C.S.D. and J.Z. contributed equally to this work.
Descrição: 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.
Editor: United States: National Academy of Sciences
Idioma: Inglês

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

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

United States: National Academy of Sciences

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