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J Med Chem. 2014 Mar 13;57(5):1694-707. doi: 10.1021/jm401312n. Epub 2013 Nov 5.

Hepatitis C virus translation inhibitors targeting the internal ribosomal entry site.

Author information

1
Department of Chemistry and Biochemistry, University of California, San Diego , 9500 Gilman Drive, La Jolla, California 92093, United States.

Abstract

The internal ribosome entry site (IRES) in the 5' 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' 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.

PMID:
24138284
PMCID:
PMC3954896
DOI:
10.1021/jm401312n
[Indexed for MEDLINE]
Free PMC Article

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