tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A
. 2021 Jul 20;118(29):e2101555118.
doi: 10.1073/pnas.2101555118.
Postinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection
Chamandi S Dampalla[SUP] 1 [/SUP], Jian Zheng[SUP] 2 [/SUP], Krishani Dinali Perera[SUP] 3 [/SUP], Lok-Yin Roy Wong[SUP] 2 [/SUP], David K Meyerholz[SUP] 4 [/SUP], Harry Nhat Nguyen[SUP] 1 [/SUP], Maithri M Kashipathy[SUP] 5 [/SUP], Kevin P Battaile[SUP] 6 [/SUP], Scott Lovell[SUP] 5 [/SUP], Yunjeong Kim[SUP] 7 [/SUP], Stanley Perlman[SUP] 8 [/SUP], William C Groutas[SUP] 9 [/SUP], Kyeong-Ok Chang[SUP] 7 [/SUP]
Affiliations
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.
Keywords: K18-ACE2 mice; SARS-CoV-2; antiviral; protease inhibitors.
. 2021 Jul 20;118(29):e2101555118.
doi: 10.1073/pnas.2101555118.
Postinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection
Chamandi S Dampalla[SUP] 1 [/SUP], Jian Zheng[SUP] 2 [/SUP], Krishani Dinali Perera[SUP] 3 [/SUP], Lok-Yin Roy Wong[SUP] 2 [/SUP], David K Meyerholz[SUP] 4 [/SUP], Harry Nhat Nguyen[SUP] 1 [/SUP], Maithri M Kashipathy[SUP] 5 [/SUP], Kevin P Battaile[SUP] 6 [/SUP], Scott Lovell[SUP] 5 [/SUP], Yunjeong Kim[SUP] 7 [/SUP], Stanley Perlman[SUP] 8 [/SUP], William C Groutas[SUP] 9 [/SUP], Kyeong-Ok Chang[SUP] 7 [/SUP]
Affiliations
- PMID: 34210738
- DOI: 10.1073/pnas.2101555118
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.
Keywords: K18-ACE2 mice; SARS-CoV-2; antiviral; protease inhibitors.