Molecular transporters for peptides: delivery of a cardioprotective ϵPKC agonist peptide into cells and intact ischemic heart using a transport system, R7 Original Research Article

Abstract Background: Recently, we reported a novel oligoguanidine transporter system, polyarginine (R7), which, when conjugated to spectroscopic probes (e.g., fluorescein) and drugs (e.g., cyclosporin A), results in highly water-soluble conjugates that rapidly enter cells and tissues. We report herein the preparation of the first R7 peptide conjugates and a study of their cellular and organ uptake and functional activity. The octapeptide ψϵRACK was selected for this study as it is known to exhibit selective ϵ protein kinase C isozyme agonist activity and to reduce ischemia-induced damage in cardiomyocytes. However, ψϵRACK is not cell-permeable. Results: Here we show that an R7-ψϵRACK conjugate readily enters cardiomyocytes, significantly outperforming ψϵRACK conjugates of the transporters derived from HIV Tat and from Antennapedia. Moreover, R7-ψϵRACK conjugate reduced ischemic damage when delivered into intact hearts either prior to or after the ischemic insult. Conclusions: Our data suggest that R7 converts a peptide lead into a potential therapeutic agent for the ischemic heart. Article Outline