9C8Q

Co-structure of Main Protease of SARS-CoV-2 (COVID-19) with covalent inhibitor

これはPDB形式変換不可エントリーです。

9C8Q の概要

• エントリーDOI: 10.2210/pdb9c8q/pdb
• 分子名称: 3C-like proteinase nsp5, (7P,8S)-3-cyclohexyl-7-(3-methylpyridin-2-yl)pyrazolo[1,5-a]pyrimidine (3 entities in total)
• 機能のキーワード: hydrolase, main protease, viral protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34117.92

構造登録者

Knapp, M.S.,Ornelas, E. (登録日: 2024-06-12, 公開日: 2024-10-16, 最終更新日: 2024-10-23)

主引用文献

Barkan, D.T.,Garland, K.,Zhang, L.,Eastman, R.T.,Hesse, M.,Knapp, M.,Ornelas, E.,Tang, J.,Cortopassi, W.A.,Wang, Y.,King, F.,Jia, W.,Nguyen, Z.,Frank, A.O.,Chan, R.,Fang, E.,Fuller, D.,Busby, S.,Carias, H.,Donahue, K.,Tandeske, L.,Diagana, T.T.,Jarrousse, N.,Moser, H.,Sarko, C.,Dovala, D.,Moquin, S.,Marx, V.M.
Identification of Potent, Broad-Spectrum Coronavirus Main Protease Inhibitors for Pandemic Preparedness.
J.Med.Chem., 67:17454-17471, 2024

PubMed Abstract: The COVID-19 pandemic highlights the ongoing risk of zoonotic transmission of coronaviruses to global health. To prepare for future pandemics, it is essential to develop effective antivirals targeting a broad range of coronaviruses. Targeting the essential and clinically validated coronavirus main protease (M), we constructed a structurally diverse M panel by clustering all known coronavirus sequences by M active site sequence similarity. Through screening, we identified a potent covalent inhibitor that engaged the catalytic cysteine of SARS-CoV-2 Mpro and used structure-based medicinal chemistry to develop compounds in the pyrazolopyrimidine sulfone series that exhibit submicromolar activity against multiple M homologues. Additionally, we solved the first X-ray cocrystal structure of M from the human-infecting OC43 coronavirus, providing insights into potency differences among compound-target pairs. Overall, the chemical compounds described in this study serve as starting points for the development of antivirals with broad-spectrum activity, enhancing our preparedness for emerging human-infecting coronaviruses.

PubMed: 39332817
DOI: 10.1021/acs.jmedchem.4c01404

実験手法

X-RAY DIFFRACTION (1.692 Å)