Hepatitis C Virus Translation Inhibitors Targeting the Internal Ribosomal Entry Site

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• 作者：Sergey M. Dibrov ; Jerod Parsons ; Maia Carnevali ; Shu Zhou ; Kevin D. Rynearson ; Kejia Ding ; Emily Garcia Sega ; Nicholas D. Brunn ; Mark A. Boerneke ; Maria P. Castaldi ; Thomas Hermann
• 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：1694-1707
• 全文大小：511K
• 年卷期：v.57,no.5(March 13, 2014)
• ISSN：1520-4804

文摘

The internal ribosome entry site (IRES) in the 5鈥?untranslated region (UTR) of the hepatitis C virus (HCV) genome initiates translation of the viral polyprotein precursor. The unique structure and high sequence conservation of the 5鈥?UTR render the IRES RNA a potential target for the development of selective viral translation inhibitors. Here, we provide an overview of approaches to block HCV IRES function by nucleic acid, peptide, and small molecule ligands. Emphasis will be given to the IRES subdomain IIa, which currently is the most advanced target for small molecule inhibitors of HCV translation. The subdomain IIa behaves as an RNA conformational switch. Selective ligands act as translation inhibitors by locking the conformation of the RNA switch. We review synthetic procedures for inhibitors as well as structural and functional studies of the subdomain IIa target and its ligand complexes.