7L7L

Crystal structure of HCV NS3/4A D168A protease in complex with NR01-129

7L7L の概要

• エントリーDOI: 10.2210/pdb7l7l/pdb
• 分子名称: NS3/4A protease, ZINC ION, 1,2-ETHANEDIOL, ... (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 complex, hydrolase/inhibitor
• 由来する生物種: Hepacivirus C
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 22332.52

構造登録者

Zephyr, J.,Schiffer, C.A. (登録日: 2020-12-29, 公開日: 2021-09-01, 最終更新日: 2023-10-18)

主引用文献

Nageswara Rao, D.,Zephyr, J.,Henes, M.,Chan, E.T.,Matthew, A.N.,Hedger, A.K.,Conway, H.L.,Saeed, M.,Newton, A.,Petropoulos, C.J.,Huang, W.,Kurt Yilmaz, N.,Schiffer, C.A.,Ali, A.
Discovery of Quinoxaline-Based P1-P3 Macrocyclic NS3/4A Protease Inhibitors with Potent Activity against Drug-Resistant Hepatitis C Virus Variants.
J.Med.Chem., 64:11972-11989, 2021

PubMed Abstract: The three pan-genotypic HCV NS3/4A protease inhibitors (PIs) currently in clinical use-grazoprevir, glecaprevir, and voxilaprevir-are quinoxaline-based P2-P4 macrocycles and thus exhibit similar resistance profiles. Using our quinoxaline-based P1-P3 macrocyclic lead compounds as an alternative chemical scaffold, we explored structure-activity relationships (SARs) at the P2 and P4 positions to develop pan-genotypic PIs that avoid drug resistance. A structure-guided strategy was used to design and synthesize two series of compounds with different P2 quinoxalines in combination with diverse P4 groups of varying sizes and shapes, with and without fluorine substitutions. Our SAR data and cocrystal structures revealed the interplay between the P2 and P4 groups, which influenced inhibitor binding and the overall resistance profile. Optimizing inhibitor interactions in the S4 pocket led to PIs with excellent antiviral activity against clinically relevant PI-resistant HCV variants and genotype 3, providing potential pan-genotypic inhibitors with improved resistance profiles.

PubMed: 34405680
DOI: 10.1021/acs.jmedchem.1c00554

実験手法

X-RAY DIFFRACTION (1.88 Å)