4MIA

Hepatitis C Virus polymerase NS5B genotype 1b (BK) in complex with RG7109 (N-{4-[6-tert-butyl-5-methoxy-8-(6-methoxy-2-oxo-2,5-dihydropyridin-3-yl)quinolin-3-yl]phenyl}methanesulfonamide)

4MIA の概要

• エントリーDOI: 10.2210/pdb4mia/pdb
• 関連するPDBエントリー: 4MIB 4MK7 4MK8 4MK9 4MKA 4MKB
• 分子名称: RNA-directed RNA polymerase, ZINC ION, N-{4-[6-tert-butyl-5-methoxy-8-(6-methoxy-2-oxo-2,5-dihydropyridin-3-yl)quinolin-3-yl]phenyl}methanesulfonamide, ... (4 entities in total)
• 機能のキーワード: polymerase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Hepatitis C virus (HCV)
• 細胞内の位置: Core protein p21: Host endoplasmic reticulum membrane; Single-pass membrane protein. Core protein p19: Virion (By similarity). Envelope glycoprotein E1: Virion membrane; Single-pass type I membrane protein (Potential). Envelope glycoprotein E2: Virion membrane; Single-pass type I membrane protein (Potential). p7: Host endoplasmic reticulum membrane; Multi-pass membrane protein (By similarity). Protease NS2-3: Host endoplasmic reticulum membrane; Multi-pass membrane protein (Potential). Serine protease NS3: Host endoplasmic reticulum membrane; Peripheral membrane protein (By similarity). Non-structural protein 4A: Host endoplasmic reticulum membrane; Single-pass type I membrane protein (Potential). Non-structural protein 4B: Host endoplasmic reticulum membrane; Multi-pass membrane protein (By similarity). Non-structural protein 5A: Host endoplasmic reticulum membrane; Peripheral membrane protein (By similarity). RNA-directed RNA polymerase: Host endoplasmic reticulum membrane; Single-pass type I membrane protein (Potential): P26663
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 127855.46

構造登録者

Harris, S.F.,Villasenor, A.G. (登録日: 2013-08-30, 公開日: 2014-05-07, 最終更新日: 2024-10-16)

主引用文献

Talamas, F.X.,Abbot, S.C.,Anand, S.,Brameld, K.A.,Carter, D.S.,Chen, J.,Davis, D.,de Vicente, J.,Fung, A.D.,Gong, L.,Harris, S.F.,Inbar, P.,Labadie, S.S.,Lee, E.K.,Lemoine, R.,Le Pogam, S.,Leveque, V.,Li, J.,McIntosh, J.,Najera, I.,Park, J.,Railkar, A.,Rajyaguru, S.,Sangi, M.,Schoenfeld, R.C.,Staben, L.R.,Tan, Y.,Taygerly, J.P.,Villasenor, A.G.,Weller, P.E.
Discovery of N-[4-[6-tert-butyl-5-methoxy-8-(6-methoxy-2-oxo-1H-pyridin-3-yl)-3-quinolyl]phenyl]methanesulfonamide (RG7109), a potent inhibitor of the hepatitis C virus NS5B polymerase.
J.Med.Chem., 57:1914-1931, 2014

PubMed Abstract: In the past few years, there have been many advances in the efforts to cure patients with hepatitis C virus (HCV). The ultimate goal of these efforts is to develop a combination therapy consisting of only direct-antiviral agents (DAAs). In this paper, we discuss our efforts that led to the identification of a bicyclic template with potent activity against the NS5B polymerase, a critical enzyme on the life cycle of HCV. In continuation of our exploration to improve the stilbene series, the 3,5,6,8-tetrasubstituted quinoline core was identified as replacement of the stilbene moiety. 6-Methoxy-2(1H)-pyridone was identified among several heterocyclic headgroups to have the best potency. Solubility of the template was improved by replacing a planar aryl linker with a saturated pyrrolidine. Profiling of the most promising compounds led to the identification of quinoline 41 (RG7109), which was selected for advancement to clinical development.

PubMed: 24195700
DOI: 10.1021/jm401329s

実験手法

X-RAY DIFFRACTION (2.8 Å)