Molecular transporters for peptides: delivery of a cardioprotective εPKC agonist peptide into cells and intact ischemic heart using a transport system, R7 |
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| Authors: | Leon Chen Lee R Wright Che-Hong Chen Steven F Oliver Paul A Wender Daria Mochly-Rosen |
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| Institution: | a Department of Molecular Pharmacology, Stanford University School of Medicine, Stanford, CA 94305-5174, USA;b Department of Chemistry, Stanford University, Stanford, CA 94305, USA |
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| 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. |
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| Keywords: | Cardiomyocyte Molecular transporter Polyarginine ψ ε RACK R7 ε PKC |
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