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

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

doi:10.1073/pnas.2101555118

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

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

Chamandi S Dampalla, Jian Zheng, Krishani Dinali Perera, Lok-Yin Roy Wong, David K Meyerholz, Harry Nhat Nguyen, Maithri M Kashipathy, Kevin P Battaile, Scott Lovell, Yunjeong Kim, …

Proceedings of the National Academy of Sciences - PNAS, Vol.118(29), p.e2101555118

07/20/2021

DOI: 10.1073/pnas.2101555118

PMCID: PMC8307543

PMID: 34210738

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Abstract

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.

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Title: Subtitle: Postinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection
Creators: Chamandi S Dampalla
Jian Zheng - University of Iowa, Microbiology and Immunology
Krishani Dinali Perera
Lok-Yin Roy Wong - University of Iowa, Microbiology and Immunology
David K Meyerholz - University of Iowa, Pathology
Harry Nhat Nguyen
Maithri M Kashipathy
Kevin P Battaile
Scott Lovell
Yunjeong Kim
Stanley Perlman - University of Iowa, Microbiology and Immunology
William C Groutas
Kyeong-Ok Chang
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.118(29), p.e2101555118
DOI: 10.1073/pnas.2101555118
PMID: 34210738
PMCID: PMC8307543
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Grant note: R01 AI109039 / HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) P01 AI060699 / HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) R01 AI129269 / HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
Language: English
Date published: 07/20/2021
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Infectious Disease (Pediatrics)
Record Identifier: 9984097082402771

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