9GV2

Crystal structure of SARS-CoV-2 main protease (MPro) in complex with the covalently bound inhibitor FP237 (compound 8p in publication)

これはPDB形式変換不可エントリーです。

9GV2 の概要

• エントリーDOI: 10.2210/pdb9gv2/pdb
• 分子名称: 3C-like proteinase nsp5, (2S)-2-[2-(3-methoxyphenoxy)ethanoylamino]-4-methyl-N-[(2S)-3-oxidanylidene-1-phenyl-pentan-2-yl]pentanamide, DIMETHYL SULFOXIDE, ... (8 entities in total)
• 機能のキーワード: protease, inhibitor, dipeptidyl inhibitors, 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: 69231.81

構造登録者

Strater, N.,Sylvester, K.,Muller, C.E.,Flury, P.,Kruger, N.,Breidenbach, J.,Guetschow, M.,Laufer, S.A.,Pillaiyar, T. (登録日: 2024-09-20, 公開日: 2025-01-29, 最終更新日: 2025-02-26)

主引用文献

Flury, P.,Kruger, N.,Sylvester, K.,Breidenbach, J.,Al Hamwi, G.,Qiao, J.,Chen, Y.,Rocha, C.,Serafim, M.S.M.,Barbosa da Silva, E.,Pohlmann, S.,Poso, A.,Kronenberger, T.,Rox, K.,O'Donoghue, A.J.,Yang, S.,Strater, N.,Gutschow, M.,Laufer, S.A.,Muller, C.E.,Pillaiyar, T.
Design, Synthesis, and Unprecedented Interactions of Covalent Dipeptide-Based Inhibitors of SARS-CoV-2 Main Protease and Its Variants Displaying Potent Antiviral Activity.
J.Med.Chem., 68:3626-3652, 2025

PubMed Abstract: The main protease (M) of SARS-CoV-2 is a key drug target for the development of antiviral therapeutics. Here, we designed and synthesized a series of small-molecule peptidomimetics with various cysteine-reactive electrophiles. Several compounds were identified as potent SARS-CoV-2 M inhibitors, including compounds (IC = 0.0752 μM), (IC = 0.0887 μM), (IC = 0.0199 μM), (IC = 0.0376 μM), (IC = 0.0177 μM), and (IC = 0.0130 μM). Most of them additionally inhibited cathepsin L and were also active against SARS-CoV-1 and MERS-CoV M. In Calu-3 cells, several inhibitors, including , , and , displayed high antiviral activity in the nanomolar range without showing cellular toxicity. The cocrystal structure of SARS-CoV-2 M in complex with revealed covalent binding to the enzyme's catalytic residue Cys145 and showed specific, unprecedented interactions within the substrate binding pocket. Compounds and especially were effective against a panel of naturally occurring nirmatrelvir-resistant mutants, particularly E166V, and showed metabolic stability and additional favorable pharmacokinetic properties, making it a suitable candidate for further preclinical development.

PubMed: 39813204
DOI: 10.1021/acs.jmedchem.4c02254

実験手法

X-RAY DIFFRACTION (2.56 Å)