RETRACTED: Selection of cyclic peptide aptamers to HCV IRES RNA using mRNA display

Abstract

The hepatitis C virus (HCV) is a positive strand RNA flavivirus that is a major causative agent of serious liver disease, making new treatment modalities an urgent priority. Because HCV translation initiation occurs by a mechanism that is fundamentally distinct from that of host mRNAs, it is an attractive target for drug discovery. The translation of HCV mRNA is initiated from an internal ribosomal entry site (IRES), independent of cap and poly(A) recognition and bypassing eIF4F complex formation. We used mRNA display selection technology combined with a simple and robust cyclization procedure to screen a peptide library of >1013 different sequences and isolate cyclic peptides that bind with high affinity and specificity to HCV IRES RNA. The best peptide binds the IRES with subnanomolar affinity, and a specificity of at least 100-fold relative to binding to several other RNAs of similar length. The peptide specifically inhibits HCV IRES-initiated translation in vitro with no detectable effect on normal cap-dependent translation initiation. An 8-aa cyclic peptide retains most of the activity of the full-length 27-aa bicyclic peptide. These peptides may be useful tools for the study of HCV translation and may have potential for further development as an anti-HCV drug.

Phage-encoded combinatorial chemical libraries based on bicyclic peptides

“…These conjugates should have advantages over other peptide forms. For example, compared to monocyclic peptides 34,35 , the bicyclic conjugates should be more capable of extensive interactions with globular proteins and perhaps thereby more able to block protein-protein interactions; compared to disulfide-bonded cyclic peptides, the cross-links should be inert to exchange and stable in reducing environments 36 ; and compared to linear peptides the conjugates should be constrained and bind more tightly to targets (due to the smaller loss of conformational entropy on binding). Indeed our literature review of the most potent peptide inhibitors isolated by phage display (Supplementary Table 2) shows that the majority are constrained by disulfide bonds.…”

Strategies for the Design of Rna-Binding Small Molecules

“…Interestingly, the peptide contained only one basic residue. Another study identified nanomolar cyclized peptide inhibitors of the hepatitis C virus (HCV) IRES RNA [90]. Peptide sequences were selected for binding to the full length (332 nucleotides) IRES and cyclized.…”

Peptide Aptamers with Biological and Therapeutic Applications

“…The study indicated that PA34 could induce a dramatic intracellular redistribution of its target protein into perinuclear inclusion bodies and lead to the typical characteristics of aggresomes, which also represents a novel mechanism as to how peptide aptamers act as intracellular inhibitors to block the function of their target proteins. Selection of peptide aptamers against the hepatitis C virus (HCV) using mRNA display has also been realized [42]. The mRNA display selection technology was combined with a simple and robust cyclization procedure to screen a peptide library and to isolate cyclic peptides that bind with high affinity and specificity to the internal ribosomal entry site (IRES) of HCV mRNA.…”