7SMV

Crystallization of feline coronavirus Mpro with GC376 reveals mechanism of inhibition

7SMV の概要

• エントリーDOI: 10.2210/pdb7smv/pdb
• 分子名称: 3C-like proteinase, N~2~-[(benzyloxy)carbonyl]-N-{(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-L-leucinamide (3 entities in total)
• 機能のキーワード: viral protein, hydrolase-hydrolase inhibitor complex, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Feline coronavirus
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 67094.05

構造登録者

Khan, M.B.,Lu, J.,Young, H.S.,Lemieux, M.J. (登録日: 2021-10-26, 公開日: 2022-04-06, 最終更新日: 2024-10-30)

主引用文献

Lu, J.,Chen, S.A.,Khan, M.B.,Brassard, R.,Arutyunova, E.,Lamer, T.,Vuong, W.,Fischer, C.,Young, H.S.,Vederas, J.C.,Lemieux, M.J.
Crystallization of Feline Coronavirus M pro With GC376 Reveals Mechanism of Inhibition.
Front Chem, 10:852210-852210, 2022

PubMed Abstract: Coronaviruses infect a variety of hosts in the animal kingdom, and while each virus is taxonomically different, they all infect their host the same mechanism. The coronavirus main protease (M, also called 3CL), is an attractive target for drug development due to its essential role in mediating viral replication and transcription. An M inhibitor, GC376, has been shown to treat feline infectious peritonitis (FIP), a fatal infection in cats caused by internal mutations in the feline enteric coronavirus (FECV). Recently, our lab demonstrated that the feline drug, GC373, and prodrug, GC376, are potent inhibitors of SARS-CoV-2 M and solved the structures in complex with the drugs; however, no crystal structures of the FIP virus (FIPV) M with the feline drugs have been published so far. Here, we present crystal structures of FIPV M-GC373/GC376 complexes, revealing the inhibitors covalently bound to Cys144 in the active site, similar to SARS-CoV-2 M. Additionally, GC376 has a higher affinity for FIPV M with lower nanomolar K values compared to SARS-CoV and SARS-CoV-2 M. We also show that improved derivatives of GC376 have higher potency for FIPV M. Since GC373 and GC376 represent strong starting points for structure-guided drug design, determining the crystal structures of FIPV M with these inhibitors are important steps in drug optimization and structure-based broad-spectrum antiviral drug discovery.

PubMed: 35281564
DOI: 10.3389/fchem.2022.852210

実験手法

X-RAY DIFFRACTION (1.93 Å)