Integrated Strategies for Identifying Leads That Target the NS3 Helicase of the Hepatitis C Virus

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• 作者：Steven R. LaPlante ; Anil K. Padyana ; Asitha Abeywardane ; Pierre Bonneau ; Mireille Cartier ; Ren茅 Coulombe ; Araz Jakalian ; Jessi Wildeson-Jones ; Xiang Li ; Shuang Liang ; Ginette McKercher ; Peter White ; Qiang Zhang ; Steven J. Taylor
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 13, 2014
• 年：2014
• 卷：57
• 期：5
• 页码：2074-2090
• 全文大小：942K
• 年卷期：v.57,no.5(March 13, 2014)
• ISSN：1520-4804

文摘

Future treatments for individuals infected by the hepatitis C virus (HCV) will likely involve combinations of compounds that inhibit multiple viral targets. The helicase of HCV is an attractive target with no known drug candidates in clinical trials. Herein we describe an integrated strategy for identifying fragment inhibitors using structural and biophysical techniques. Based on an X-ray structure of apo HCV helicase and in silico and bioinformatic analyses of HCV variants, we identified that one site in particular (labeled 3 + 4) was the most conserved and attractive pocket to target for a drug discovery campaign. Compounds from multiple sources were screened to identify inhibitors or binders to this site, and enzymatic and biophysical assays (NMR and SPR) were used to triage the most promising ligands for 3D structure determination by X-ray crystallography. Medicinal chemistry and biophysical evaluations focused on exploring the most promising lead series. The strategies employed here can have general utility in drug discovery.