Structure-Based Discovery of Triphenylmethane Derivatives as Inhibitors of Hepatitis C Virus Helicase

• Published in: Journal of medicinal chemistry Vol. 52; no. 9; pp. 2716 - 2723
• Main Authors: Chen, Chien-Shu, Chiou, Chun-Tang, Chen, Grace Shiahuy, Chen, Sheng-Chia, Hu, Chih-Yung, Chi, Wei-Kuang, Chu, Yi-Ding, Hwang, Lih-Hwa, Chen, Pei-Jer, Chen, Ding-Shinn, Liaw, Shwu-Huey, Chern, Ji-Wang
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.05.2009; Amer Chemical Soc
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Binding Sites; Biological and medical sciences; Cell Line; Cell Proliferation - drug effects; Chemistry, Medicinal; Drug Discovery; Drug Evaluation, Preclinical; Hepacivirus - drug effects; Hepacivirus - enzymology; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Replicon - drug effects; Science & Technology; Software; Trityl Compounds - chemistry; Trityl Compounds - pharmacology; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - chemistry; NS3 RNA HELICASE; SERINE-PROTEASE INHIBITORS; DOMAIN; REPLICATION; MODE; RESISTANCE; MUTATIONAL ANALYSIS; STRATEGIES; Molecular structure; Halophenols; Liver; Cytotoxicity; Binding site; Modeling; Molecular model; Antiviral; Bromine Organic compounds; Chemical synthesis; Tumor cell; Human; Enzyme; Transferases; Virtual screening; X ray diffraction; In vitro; Biological activity; Virus; Nucleotidyltransferases; Cell line; Flaviviridae; Hepatitis C virus; Hepacivirus; Replicon; Crystalline structure
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm8011905

Hepatitis C virus nonstructural protein 3 (HCV NS3) helicase is believed to be essential for viral replication and has become an attractive target for the development of antiviral drugs. A fluorescence resonant energy transfer helicase assay was established for fast screening of putative inhibitors selected from virtual screening using the program DOCK. Soluble blue HT (1) was first identified as a novel HCV helicase inhibitor. Crystal structure of the NS3 helicase in complex with soluble blue HT shows that the inhibitor bears a significantly higher binding affinity mainly through a 4-sulfonatophenylaminophenyl group, and this is consistent with the activity assay. Subsequently, fragment-based searches were utilized to identify triphenylmethane derivatives for more potent inhibitors. Lead optimization resulted in a 3-bromo-4-hydroxyl substituted derivative 12 with an EC50 value of 2.72 μM to Ava.5/Huh-7 cells and a lower cytotoxicity to parental Huh-7 cells (CC50 = 10.5 μM), and it indeed suppressed HCV replication in the HCV replicon cells. Therefore, these inhibitors with structural novelty may serve as a useful scaffold for the discovery of new HCV NS3 helicase inhibitors.