Catalytic metallodrugs based on the LaR2C peptide target HCV SLIV IRES RNA.

Prior work has demonstrated the potential effectiveness of a new class of metallopeptides as catalytic metallodrugs that target HCV IRES SLIIb RNA (Cu-GGHYrFK, 1). Herein new catalytic metallodrugs (GGHKYKETDLLILFKDDYFAKKNEERK, 2; and GGHKYKETDL, 3) are described based on the LaR2C peptide that has been shown to bind to the SLIV HCV IRES domain. In vitro fluorescence assays yielded KD values ∼10 μM for both peptides and reaction of the copper derivatives with SLIV RNA demonstrated initial rates comparable across different assays as well as displaying pseudo-Michaelis-Menten behavior.

Insight into the recognition, binding, and reactivity of catalytic metallodrugs targeting stem loop IIb of hepatitis C IRES RNA.

The complex Cu-GGHYrFK-amide (1-Cu) was previously reported as a novel metallotherapeutic that catalytically inactivates stem loop IIb (SLIIb) of the hepatitis C virus (HCV) internal ribosomal entry site (IRES) RNA and demonstrates significant antiviral activity in a cellular HCV replicon assay. Herein we describe additional studies focused on understanding the cleavage mechanism as well as the relationship of catalyst configuration to structural recognition and site-selective cleavage of the structured RNA motif. These are advanced by use of a combination of MALDI-TOF mass spectrometry, melting temperature determinations, and computational analysis to develop a structural model for binding and reactivity toward SLIIb of the IRES RNA.