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

Martin James Ross, Seth S Bradford, J A Cowan

Index: Dalton Trans. 44 , 20972-82, (2015)

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Abstract

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. The sites of reaction and cleavage mechanisms were determined by MALDI-TOF mass spectrometry. The primary site of copper-promoted SLIV cleavage is shown to occur in the vicinity of the 5'-G17C18A19C20-3' sequence that corresponds to a known binding site of the RM2 motif of the human La protein and has previously been reported to be important for viral translation. This domain also flanks the internal start codon (AUG). Both copper complexes also showed efficacy in an HCV replicon assay (IC50 = 0.75 μM for 2-Cu, and 2.17 μM for 3-Cu) and show potential for treatment of hepatitis C, complementing other marketed drugs by acting on a distinct therapeutic target by a novel mechanism of action.