7Q5F

Crystal structure of F2F-2020216-01X bound to the main protease (3CLpro/Mpro) of SARS-CoV-2.

7Q5F の概要

• エントリーDOI: 10.2210/pdb7q5f/pdb
• 分子名称: 3C-like proteinase, (S)-1-(2-(2,4-dichlorophenoxy)acetyl)-N-((S)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)-4-(phenethylamino)butan-2-yl)pyrrolidine-2-carboxamide, SULFATE ION, ... (8 entities in total)
• 機能のキーワード: sars-cov-2, mpro, 3clpro, exscalate4cov, drug discovery, elettra, viral protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 69334.21

構造登録者

Costanzi, E.,Demitri, N.,Storici, P. (登録日: 2021-11-03, 公開日: 2022-11-23, 最終更新日: 2024-11-06)

主引用文献

Pelliccia, S.,Cerchia, C.,Esposito, F.,Cannalire, R.,Corona, A.,Costanzi, E.,Kuzikov, M.,Gribbon, P.,Zaliani, A.,Brindisi, M.,Storici, P.,Tramontano, E.,Summa, V.
Easy access to alpha-ketoamides as SARS-CoV-2 and MERS M pro inhibitors via the PADAM oxidation route.
Eur.J.Med.Chem., 244:114853-114853, 2022

PubMed Abstract: SARS-CoV-2 caused worldwide the current outbreak called COVID-19. Despite multiple countermeasures implemented, there is an urgent global need for new potent and efficient antiviral drugs against this pathogen. In this context, the main protease (M) of SARS-CoV-2 is an essential viral enzyme and plays a pivotal role in viral replication and transcription. Its specific cleavage of polypeptides after a glutamine residue has been considered as a key element to design novel antiviral drugs. Herein, we reported the design, synthesis and structure-activity relationships of novel α-ketoamides as covalent reversible inhibitors of M, exploiting the PADAM oxidation route. The reported compounds showed μM to nM activities in enzymatic and in the antiviral cell-based assays against SARS-CoV-2 M. In order to assess inhibitors' binding mode, two co-crystal structures of SARS-CoV-2 M in complex with our inhibitors were solved, which confirmed the covalent binding of the keto amide moiety to the catalytic Cys145 residue of M. Finally, in order to interrogate potential broad-spectrum properties, we assessed a selection of compounds against MERS M where they showed nM inhibitory potency, thus highlighting their potential as broad-spectrum coronavirus inhibitors.

PubMed: 36332546
DOI: 10.1016/j.ejmech.2022.114853

実験手法

X-RAY DIFFRACTION (1.72 Å)