Premium
Selection of cyclic peptide aptamers to HCV IRES RNA using mRNA display
Author(s) -
Litovchick Alexander,
Szostak Jack W
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.338
Subject(s) - internal ribosome entry site , translation (biology) , peptide , rna , biology , hepatitis c virus , messenger rna , eukaryotic translation , virology , microbiology and biotechnology , virus , gene , biochemistry
The hepatitis C virus (HCV) is a major causative agent of a serious liver disease, infecting over170 mln people around the world. Eradication of hepatitis C virus is a challenging goal for antiviral pharmaceutical research. A highly conserved 341‐nucleotide 5' non‐translated region of HCV genome, an internal ribosomal entry site (IRES), mediates the initiation of translation of the viral polyprotein in a cap‐ and poly (A)‐independent way. Translation initiation from HCV IRES occurs by a mechanism, fundamentally distinct from host mRNAs, which makes it an attractive target for drug discovery. We have utilized an mRNA display selection technology to isolate high affinity and specificity peptide binders to HCV IRES RNA. A simple and robust method for posttranslational cyclization, the reaction of two cysteine sulfhydryls with dibromo xylene, was utilized to generate a cyclic peptide‐mRNA fusion library. Starting with over 10 13 different peptide sequences, we isolated the bicyclic peptide 6B4C, which binds the IRES with subnanomolar affinity, and demonstrates remarkable activity and specificity of the inhibition of the HCV IRES‐initiated translation of Luciferase reporter gene in vitro . The minimal active region of the peptide is a loop of 8 amino acid residues. The 6B4C peptide could serve a useful specific tool for study HCV translation as well as possesses a potential for further development as an anti‐HCV drug.