7K0H
1.70 A resolution structure of SARS-CoV 3CL protease in complex with a deuterated GC376 alpha-ketoamide analog (compound 5)
Summary for 7K0H
| Entry DOI | 10.2210/pdb7k0h/pdb |
| Descriptor | Replicase polyprotein 1a, CHLORIDE ION, N-{(2S,3R)-4-(benzylamino)-3-hydroxy-4-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl}-N~2~-[(benzyloxy)carbonyl]-L-leucinamide, ... (5 entities in total) |
| Functional Keywords | protease, severe acute respiratory syndrome coronavirus, sars 3cl protease inhhibitors, hydrolase, deuterated hydrolase inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Human SARS coronavirus (SARS-CoV) |
| Total number of polymer chains | 2 |
| Total formula weight | 70263.00 |
| 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: 2021-07-07, Last modification date: 2023-10-18) |
| 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 Cited by 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: 34210738DOI: 10.1073/pnas.2101555118 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.7 Å) |
Structure validation
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