3TYQ

SAR development and discovery of potent indole-based inhibitors of the hepatitis c virus NS5B polymerase

Summary for 3TYQ

• Entry DOI: 10.2210/pdb3tyq/pdb
• Related: 3TYV
• Descriptor: RNA-directed RNA polymerase, 5-ethyl-1-(2-fluoro-5-nitrobenzyl)-3-(2-oxo-1,2-dihydropyridin-3-yl)-1H-indole-2-carboxylic acid, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: rna-dependent rna polymerase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Hepatitis C virus (HCV)
• Cellular location: Core protein p21: Host endoplasmic reticulum membrane; Single-pass membrane protein (By similarity). 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): O92972
• Total number of polymer chains: 2
• Total formula weight: 129538.89

Authors

Lesburg, C.A.,Chen, K.X. (deposition date: 2011-09-26, release date: 2012-02-01, Last modification date: 2024-02-28)

Primary citation

Chen, K.X.,Lesburg, C.A.,Vibulbhan, B.,Yang, W.,Chan, T.Y.,Venkatraman, S.,Velazquez, F.,Zeng, Q.,Bennett, F.,Anilkumar, G.N.,Duca, J.,Jiang, Y.,Pinto, P.,Wang, L.,Huang, Y.,Selyutin, O.,Gavalas, S.,Pu, H.,Agrawal, S.,Feld, B.,Huang, H.C.,Li, C.,Cheng, K.C.,Shih, N.Y.,Kozlowski, J.A.,Rosenblum, S.B.,Njoroge, F.G.
A Novel Class of Highly Potent Irreversible Hepatitis C Virus NS5B Polymerase Inhibitors.
J.Med.Chem., 55:2089-2101, 2012

PubMed Abstract: Starting from indole-based C-3 pyridone HCV NS5B polymerase inhibitor 2, structure-activity relationship (SAR) investigations of the indole N-1 benzyl moiety were performed. This study led to the discovery of irreversible inhibitors with p-fluoro-sulfone- or p-fluoro-nitro-substituted N-1 benzyl groups which achieved breakthrough replicon assay potency (EC(50) = 1 nM). The formation of a covalent bond with adjacent cysteine-366 thiol was was proved by mass spectroscopy and X-ray crystal structure studies. The C-5 ethyl C-2 carboxylic acid derivative 47 had an excellent oral area-under-the-curve (AUC) of 18 μM·h (10 mg/kg). Its oral exposure in monkeys and dogs was also very good. The NMR ALARM assay, mass spectroscopy experiments, in vitro counter screening, and toxicology assays demonstrated that the covalent bond formation between compound 47 and the protein was highly selective and specific. The overall excellent profile of 47 made it an interesting candidate for further investigation.

PubMed: 22247956
DOI: 10.1021/jm201322r

Experimental method

X-RAY DIFFRACTION (1.6 Å)