7FAY

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

7FAY の概要

• エントリーDOI: 10.2210/pdb7fay/pdb
• 分子名称: 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)
• 機能のキーワード: coronavirus, protease, inhibitor, complex, viral protein., viral protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34237.08

構造登録者

Zeng, R.,Quan, B.X.,Liu, X.L.,Lei, J. (登録日: 2021-07-08, 公開日: 2021-07-21, 最終更新日: 2024-10-16)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.1 Å)