6MVO

HCV NS5B 1A Y316 bound to Compound 49

6MVO の概要

• エントリーDOI: 10.2210/pdb6mvo/pdb
• 関連するPDBエントリー: 6MVK 6MVP 6MVQ
• 分子名称: RNA-directed RNA polymerase, SULFATE ION, 6-[(7-chloro-1-hydroxy-1,3-dihydro-2,1-benzoxaborol-5-yl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-1-benzofuran-3-carboxamide, ... (4 entities in total)
• 機能のキーワード: hepatitus c, ns5b, replication, viral protein
• 由来する生物種: Hepacivirus C
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 125808.04

構造登録者

Williams, S.P.,Kahler, K.,Price, D.J.,Peat, A.J. (登録日: 2018-10-26, 公開日: 2019-09-04, 最終更新日: 2024-03-13)

主引用文献

Chong, P.Y.,Shotwell, J.B.,Miller, J.,Price, D.J.,Maynard, A.,Voitenleitner, C.,Mathis, A.,Williams, S.,Pouliot, J.J.,Creech, K.,Wang, F.,Fang, J.,Zhang, H.,Tai, V.W.,Turner, E.,Kahler, K.M.,Crosby, R.,Peat, A.J.
Design of N-Benzoxaborole Benzofuran GSK8175-Optimization of Human Pharmacokinetics Inspired by Metabolites of a Failed Clinical HCV Inhibitor.
J.Med.Chem., 62:3254-3267, 2019

PubMed Abstract: We previously described the discovery of GSK5852 (1), a non-nucleoside polymerase (NS5B) inhibitor of hepatitis C virus (HCV), in which an N-benzyl boronic acid was essential for potent antiviral activity. Unfortunately, facile benzylic oxidation resulted in a short plasma half-life (5 h) in human volunteers, and a backup program was initiated to remove metabolic liabilities associated with 1. Herein, we describe second-generation NS5B inhibitors including GSK8175 (49), a sulfonamide- N-benzoxaborole analog with low in vivo clearance across preclinical species and broad-spectrum activity against HCV replicons. An X-ray structure of NS5B protein cocrystallized with 49 revealed unique protein-inhibitor interactions mediated by an extensive network of ordered water molecules and the first evidence of boronate complex formation within the binding pocket. In clinical studies, 49 displayed a 60-63 h half-life and a robust decrease in viral RNA levels in HCV-infected patients, thereby validating our hypothesis that reducing benzylic oxidation would improve human pharmacokinetics and lower efficacious doses relative to 1.

PubMed: 30763090
DOI: 10.1021/acs.jmedchem.8b01719

実験手法

X-RAY DIFFRACTION (1.95 Å)