7FAY

Crystal structure of SARS-CoV-2 main protease in complex with (R)-1a

Summary for 7FAY

• Entry DOI: 10.2210/pdb7fay/pdb
• Descriptor: 3C-like proteinase, (2~{R})-~{N}-[(1~{R})-2-(~{tert}-butylamino)-2-oxidanylidene-1-pyridin-3-yl-ethyl]-~{N}-(4-~{tert}-butylphenyl)-2-oxidanyl-propanamide (3 entities in total)
• Functional Keywords: coronavirus, protease, inhibitor, complex, viral protein., viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV)
• Total number of polymer chains: 1
• Total formula weight: 34237.08

Authors

Zeng, R.,Quan, B.X.,Liu, X.L.,Lei, J. (deposition date: 2021-07-08, release date: 2021-07-21, Last modification date: 2024-10-16)

Primary citation

Quan, B.X.,Shuai, H.,Xia, A.J.,Hou, Y.,Zeng, R.,Liu, X.L.,Lin, G.F.,Qiao, J.X.,Li, W.P.,Wang, F.L.,Wang, K.,Zhou, R.J.,Yuen, T.T.,Chen, M.X.,Yoon, C.,Wu, M.,Zhang, S.Y.,Huang, C.,Wang, Y.F.,Yang, W.,Tian, C.,Li, W.M.,Wei, Y.Q.,Yuen, K.Y.,Chan, J.F.,Lei, J.,Chu, H.,Yang, S.
An orally available M pro inhibitor is effective against wild-type SARS-CoV-2 and variants including Omicron.
Nat Microbiol, 7:716-725, 2022

PubMed Abstract: Emerging SARS-CoV-2 variants continue to cause waves of new infections globally. Developing effective antivirals against SARS-CoV-2 and its variants is an urgent task. The main protease (M) of SARS-CoV-2 is an attractive drug target because of its central role in viral replication and its conservation among variants. We herein report a series of potent α-ketoamide-containing M inhibitors obtained using the Ugi four-component reaction. The prioritized compound, Y180, showed an IC of 8.1 nM against SARS-CoV-2 M and had oral bioavailability of 92.9%, 31.9% and 85.7% in mice, rats and dogs, respectively. Y180 protected against wild-type SARS-CoV-2, B.1.1.7 (Alpha), B.1.617.1 (Kappa) and P.3 (Theta), with EC of 11.4, 20.3, 34.4 and 23.7 nM, respectively. Oral treatment with Y180 displayed a remarkable antiviral potency and substantially ameliorated the virus-induced tissue damage in both nasal turbinate and lung of B.1.1.7-infected K18-human ACE2 (K18-hACE2) transgenic mice. Therapeutic treatment with Y180 improved the survival of mice from 0 to 44.4% (P = 0.0086) upon B.1.617.1 infection in the lethal infection model. Importantly, Y180 was also highly effective against the B.1.1.529 (Omicron) variant both in vitro and in vivo. Overall, our study provides a promising lead compound for oral drug development against SARS-CoV-2.

PubMed: 35477751
DOI: 10.1038/s41564-022-01119-7

Experimental method

X-RAY DIFFRACTION (2.1 Å)