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

doi:10.1073/pnas.2101555118

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

Journal Article · Thu Jul 01 04:00:00 EDT 2021 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.2101555118· OSTI ID:1816161

^[1]; Zheng, Jian ^[2]; ^[3]; ^[2]; ^[4]; Nguyen, Harry Nhat ^[5]; Kashipathy, Maithri M. ^[6]; ^[7]; ^[6]; ^[3]; ^[2]; Groutas, William C. ^[5]; Chang, Kyeong-Ok ^[3]

Wichita State Univ., Wichita, KS (United States). Dept. of Chemistry; OSTI
Univ. of Iowa, Iowa City, IA (United States). Dept. of Microbiology and Immunology
Kansas State Univ., Manhattan, KS (United States). College of Veterinary Medicine. Dept. of Diagnostic Medicine and Pathobiology
Univ. of Iowa, Iowa City, IA (United States). Dept. of Pathology
Wichita State Univ., Wichita, KS (United States). Dept. of Chemistry
Univ. of Kansas, Lawrence, KS (United States). Protein Strucutre Lab.
New York Structural Biology Center, Upton, NY (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division

Grant/Contract Number:: AC02-06CH11357; SC0012704

OSTI ID:: 1816161

Alternate ID(s):: OSTI ID: 1809009
OSTI ID: 1826764

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 29 Vol. 118; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
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protease inhibitors

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

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