Open AccessPostinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection
Author(s) -
Chamandi S. Dampalla,
Jian Zheng,
Krishani Dinali Perera,
Lok-Yin Roy Wong,
David K. Meyerholz,
Harry Nhat Nguyen,
M.M. Kashipathy,
Kevin P. Battaile,
Scott Lovell,
Yun-Jeong Kim,
Stanley Perlman,
William C. Groutas,
KyeongOk Chang
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2101555118
Subject(s) - protease , virology , vero cell , virus , viral replication , biology , protease inhibitor (pharmacology) , enzyme , coronavirus , titer , covid-19 , nidovirales , microbiology and biotechnology , pharmacology , viral load , medicine , biochemistry , pathology , infectious disease (medical specialty) , disease , antiretroviral therapy
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.