5VOJ

Crystal structure of HCV NS3/4A protease in complex with JZ01-15, an analogue of 5172-mcP1P3

5VOJ の概要

• エントリーDOI: 10.2210/pdb5voj/pdb
• 関連するPDBエントリー: 5vp9
• 分子名称: NS4A cofactor -- NS3 protein chimera, tert-butyl [(2R,6S,12Z,13aS,14aR,16aS)-2-[(7-methoxy-3-methylquinoxalin-2-yl)oxy]-14a-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl]carbamate, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: ns3/4a protease, hepatitis c virus, drug resistance, protease inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Hepatitis C virus subtype 1a; 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 22419.69

構造登録者

Matthew, A.N.,Schiffer, C.A. (登録日: 2017-05-03, 公開日: 2017-06-21, 最終更新日: 2023-10-04)

主引用文献

Matthew, A.N.,Zephyr, J.,Hill, C.J.,Jahangir, M.,Newton, A.,Petropoulos, C.J.,Huang, W.,Kurt-Yilmaz, N.,Schiffer, C.A.,Ali, A.
Hepatitis C Virus NS3/4A Protease Inhibitors Incorporating Flexible P2 Quinoxalines Target Drug Resistant Viral Variants.
J. Med. Chem., 60:5699-5716, 2017

PubMed Abstract: A substrate envelope-guided design strategy is reported for improving the resistance profile of HCV NS3/4A protease inhibitors. Analogues of 5172-mcP1P3 were designed by incorporating diverse quinoxalines at the P2 position that predominantly interact with the invariant catalytic triad of the protease. Exploration of structure-activity relationships showed that inhibitors with small hydrophobic substituents at the 3-position of P2 quinoxaline maintain better potency against drug resistant variants, likely due to reduced interactions with residues in the S2 subsite. In contrast, inhibitors with larger groups at this position were highly susceptible to mutations at Arg155, Ala156, and Asp168. Excitingly, several inhibitors exhibited exceptional potency profiles with EC values ≤5 nM against major drug resistant HCV variants. These findings support that inhibitors designed to interact with evolutionarily constrained regions of the protease, while avoiding interactions with residues not essential for substrate recognition, are less likely to be susceptible to drug resistance.

PubMed: 28594175
DOI: 10.1021/acs.jmedchem.7b00426

実験手法

X-RAY DIFFRACTION (1.799 Å)