7ZQV

Structure of the SARS-CoV-2 main protease in complex with AG7404

7ZQV の概要

• エントリーDOI: 10.2210/pdb7zqv/pdb
• 関連するPDBエントリー: 7P35 7ZQW
• 分子名称: 3C-like proteinase nsp5, ethyl (4R)-4-({(2S)-2-[3-{[(5-methyl-1,2-oxazol-3-yl)carbonyl]amino}-2-oxopyridin-1(2H)-yl]pent-4-ynoyl}amino)-5-[(3S)-2-oxopyrrolidin-3-yl]pentanoate (3 entities in total)
• 機能のキーワード: protease, inhibitor, sars-cov-2, 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: 2
• 化学式量合計: 68702.20

構造登録者

Fabrega-Ferrer, M.,Herrera-Morande, A.,Perez-Saavedra, J.,Coll, M. (登録日: 2022-05-03, 公開日: 2022-12-28, 最終更新日: 2024-10-23)

主引用文献

Fabrega-Ferrer, M.,Herrera-Morande, A.,Muriel-Goni, S.,Perez-Saavedra, J.,Bueno, P.,Castro, V.,Garaigorta, U.,Gastaminza, P.,Coll, M.
Structure and inhibition of SARS-CoV-1 and SARS-CoV-2 main proteases by oral antiviral compound AG7404.
Antiviral Res., 208:105458-105458, 2022

PubMed Abstract: Severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2) pose a threat to global public health. The 3C-like main protease (M), which presents structural similarity with the active site domain of enterovirus 3C protease, is one of the best-characterized drug targets of these viruses. Here we studied the antiviral activity of the orally bioavailable enterovirus protease inhibitor AG7404 against SARS-CoV-1 and SARS-CoV-2 from a structural, biochemical, and cellular perspective, comparing it with the related molecule rupintrivir (AG7800). Crystallographic structures of AG7404 in complex with SARS-CoV-1 M and SARS-CoV-2 M and of rupintrivir in complex with SARS-CoV-2 M were solved, revealing that all protein residues interacting with the inhibitors are conserved between the two proteins. A detailed analysis of protein-inhibitor interactions indicates that AG7404 has a better fit to the active site of the target protease than rupintrivir. This observation was further confirmed by biochemical FRET assays showing IC values of 47 μM and 101 μM for AG7404 and rupintrivir, respectively, in the case of SARS-CoV-2 M. Equivalent IC values for SARS-CoV-1 also revealed greater inhibitory capacity of AG7404, with a value of 29 μM vs. 66 μM for rupintrivir. Finally, the antiviral activity of the two inhibitors against SARS-CoV-2 was confirmed in a human cell culture model of SARS-CoV-2 infection, although rupintrivir showed a higher potency and selectivity index in this assay.

PubMed: 36336176
DOI: 10.1016/j.antiviral.2022.105458

実験手法

X-RAY DIFFRACTION (2.26 Å)