6W2A

1.65 A resolution structure of SARS-CoV 3CL protease in complex with inhibitor 7j

Summary for 6W2A

• Entry DOI: 10.2210/pdb6w2a/pdb
• Descriptor: Replicase polyprotein 1a, [4,4-bis(fluoranyl)cyclohexyl]methyl ~{N}-[(2~{S})-1-[[(1~{R},2~{S})-1-[bis(oxidanyl)-oxidanylidene-$l^{5}-sulfanyl]-1-oxidanyl-3-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxidanylidene-pentan-2-yl]carbamate, (1S,2S)-2-[(N-{[(4,4-difluorocyclohexyl)methoxy]carbonyl}-L-leucyl)amino]-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid, ... (4 entities in total)
• Functional Keywords: protease, severe acute respiratory syndrome coronavirus, sars 3cl protease inhhibitors, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human SARS coronavirus (SARS-CoV)
• Total number of polymer chains: 2
• Total formula weight: 71030.91

Authors

Kashipathy, M.M.,Lovell, S.,Battaile, K.P.,Rathnayake, A.D.,Zheng, J.,Kim, Y.,Nguyen, H.N.,Chang, K.O.,Groutas, W.C. (deposition date: 2020-03-05, release date: 2020-08-12, Last modification date: 2024-10-09)

Primary citation

Rathnayake, A.D.,Zheng, J.,Kim, Y.,Perera, K.D.,Mackin, S.,Meyerholz, D.K.,Kashipathy, M.M.,Battaile, K.P.,Lovell, S.,Perlman, S.,Groutas, W.C.,Chang, K.O.
3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV-infected mice.
Sci Transl Med, 12:-, 2020

PubMed Abstract: Pathogenic coronaviruses are a major threat to global public health, as exemplified by severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and the newly emerged SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19). We describe herein the structure-guided optimization of a series of inhibitors of the coronavirus 3C-like protease (3CLpro), an enzyme essential for viral replication. The optimized compounds were effective against several human coronaviruses including MERS-CoV, SARS-CoV, and SARS-CoV-2 in an enzyme assay and in cell-based assays using Huh-7 and Vero E6 cell lines. Two selected compounds showed antiviral effects against SARS-CoV-2 in cultured primary human airway epithelial cells. In a mouse model of MERS-CoV infection, administration of a lead compound 1 day after virus infection increased survival from 0 to 100% and reduced lung viral titers and lung histopathology. These results suggest that this series of compounds has the potential to be developed further as antiviral drugs against human coronaviruses.

PubMed: 32747425
DOI: 10.1126/scitranslmed.abc5332

Experimental method

X-RAY DIFFRACTION (1.65 Å)