7K0F

1.65 A resolution structure of SARS-CoV-2 3CL protease in complex with a deuterated GC376 alpha-ketoamide analog (compound 5)

Summary for 7K0F

• Entry DOI: 10.2210/pdb7k0f/pdb
• Descriptor: 3C-like proteinase, N-{(2S,3R)-4-(benzylamino)-3-hydroxy-4-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl}-N~2~-[(benzyloxy)carbonyl]-L-leucinamide, TETRAETHYLENE GLYCOL, ... (4 entities in total)
• Functional Keywords: covid-19, protease, severe acute respiratory syndrome coronavirus 2, sars-cov-2 3cl protease inhhibitors, hydrolase, deuterated hydrolase inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV)
• Total number of polymer chains: 2
• Total formula weight: 69409.11

Authors

Lovell, S.,Kashipathy, M.M.,Battaile, K.P.,Chamandi, S.D.,Nguyen, H.N.,Kim, Y.,Chang, K.O.,Groutas, W.C. (deposition date: 2020-09-04, release date: 2021-01-13, Last modification date: 2024-11-06)

Primary citation

Dampalla, C.S.,Zheng, J.,Perera, K.D.,Wong, L.R.,Meyerholz, D.K.,Nguyen, H.N.,Kashipathy, M.M.,Battaile, K.P.,Lovell, S.,Kim, Y.,Perlman, S.,Groutas, W.C.,Chang, K.O.
Postinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

PubMed 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.

PubMed: 34210738
DOI: 10.1073/pnas.2101555118

Experimental method

X-RAY DIFFRACTION (1.65 Å)