8TPE

Synthesis, X-Ray Crystallographic and Biological Activities of Covalent, Non-Peptidic Inhibitors of SARS-CoV-2 Main Protease

8TPE の概要

• エントリーDOI: 10.2210/pdb8tpe/pdb
• 分子名称: Non-structural protein 7, N-[(1R)-2-(benzylamino)-2-oxo-1-(pyridin-3-yl)ethyl]-N-(4-tert-butylphenyl)-3-hydroxypropanamide (3 entities in total)
• 機能のキーワード: non-peptidic inhibitors, inhibitors, sars-cov-2, main protease, mpro, viral protein, viral protein-inhibitor complex, viral protein/inhibitor
• 由来する生物種: Severe acute respiratory syndrome coronavirus (2019-nCoV, SARS-CoV-2)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 68285.94

構造登録者

Chua, T.K.,Song, Y. (登録日: 2023-08-04, 公開日: 2024-01-24, 最終更新日: 2024-10-23)

主引用文献

Ashraf-Uz-Zaman, M.,Chua, T.K.,Li, X.,Yao, Y.,Moku, B.K.,Mishra, C.B.,Avadhanula, V.,Piedra, P.A.,Song, Y.
Design, Synthesis, X-ray Crystallography, and Biological Activities of Covalent, Non-Peptidic Inhibitors of SARS-CoV-2 Main Protease.
Acs Infect Dis., 10:715-731, 2024

PubMed Abstract: Highly contagious SARS-CoV-2 coronavirus has infected billions of people worldwide with flu-like symptoms since its emergence in 2019. It has caused deaths of several million people. The viral main protease (Mpro) is essential for SARS-CoV-2 replication and therefore a drug target. Several series of covalent inhibitors of Mpro were designed and synthesized. Structure-activity relationship studies show that (1) several chloroacetamide- and epoxide-based compounds targeting Cys145 are potent inhibitors with IC values as low as 0.49 μM and (2) Cys44 of Mpro is not nucleophilic for covalent inhibitor design. High-resolution X-ray studies revealed the protein-inhibitor interactions and mechanisms of inhibition. It is of interest that Cys145 preferably attacks the more hindered C atom of several epoxide inhibitors. Chloroacetamide inhibitor and epoxide inhibitor were found to inhibit cellular SARS-CoV-2 replication with an EC (half-log reduction of virus titer) of 3 and 5 μM. These compounds represent new pharmacological leads for anti-SARS-CoV-2 drug development.

PubMed: 38192109
DOI: 10.1021/acsinfecdis.3c00565

実験手法

X-RAY DIFFRACTION (1.61 Å)