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

Background: Recently, we reported a novel oligoguanidine transporter system, polyarginine (R-7), 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 psiepsilonRACK was selected for this study as it is known to exhibit selective e protein kinase C isozyme agonist activity and to reduce ischemia-induced damage in cardiomyocytes. However, psiepsilonRACK is not cell-permeable. Results: Here we show that an R-7-psiepsilonRACK conjugate readily enters cardiomyocytes, significantly outperforming psiepsilonRACK conjugates of the transporters derived from HIV Tat and from Antennapedia. Moreover, R-7-psiepsilonRACK 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. (C) 2001 Elsevier Science Ltd. All rights reserved.