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

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.

SUBMITTER: Ross MJ

PROVIDER: S-EPMC4691540 | biostudies-other | 2015 Dec

REPOSITORIES: biostudies-other

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

Ross Martin James MJ Bradford Seth S SS Cowan J A JA

Dalton transactions (Cambridge, England : 2003) 20151119 48

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 ...[more]

PMID: 26583601

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Project description:The lack of small animal models for hepatitis C virus has impeded the discovery and development of anti-HCV drugs. HCV-IRES plays an important role in HCV gene expression, and is an attractive target for antiviral therapy. In this study, we report a zebrafish model with a biscistron expression construct that can co-transcribe GFP and HCV-core genes by human hepatic lipase promoter and zebrafish liver fatty acid binding protein enhancer. HCV core translation was designed mediated by HCV-IRES sequence and gfp was by a canonical cap-dependent mechanism. Results of fluorescence image and in situ hybridization indicate that expression of HCV core and GFP is liver-specific; RT-PCR and Western blotting show that both core and gfp expression are elevated in a time-dependent manner for both transcription and translation. It means that the HCV-IRES exerted its role in this zebrafish model. Furthermore, the liver-pathological impact associated with HCV-infection was detected by examination of gene markers and some of them were elevated, such as adiponectin receptor, heparanase, TGF-β, PDGF-α, etc. The model was used to evaluate three clinical drugs, ribavirin, IFNα-2b and vitamin B12. The results show that vitamin B12 inhibited core expression in mRNA and protein levels in dose-dependent manner, but failed to impact gfp expression. Also VB12 down-regulated some gene transcriptions involved in fat liver, liver fibrosis and HCV-associated pathological process in the larvae. It reveals that HCV-IRES responds to vitamin B12 sensitively in the zebrafish model. Ribavirin did not disturb core expression, hinting that HCV-IRES is not a target site of ribavirin. IFNα-2b was not active, which maybe resulted from its degradation in vivo for the long time. These findings demonstrate the feasibility of the zebrafish model for screening of anti-HCV drugs targeting to HCV-IRES. The zebrafish system provides a novel evidence of using zebrafish as a HCV model organism.

Dataset Information

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

Publications

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

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