Molecular transporters for peptides: delivery of a cardioprotective epsilonPKC agonist peptide into cells and intact ischemic heart using a transport system, R(7).
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 R(7) peptide conjugates and a study of their cellular and organ uptake and functional activity. The octapeptide (psi)(epsilon)RACK was selected for this study as it is known to exhibit selective epsilon protein kinase C isozyme agonist activity and to reduce ischemia-induced damage in cardiomyocytes. However, (psi)(epsilon)RACK is not cell-permeable.


RESULTS
Here we show that an R(7)-(psi)(epsilon)RACK conjugate readily enters cardiomyocytes, significantly outperforming (psi)(epsilon)RACK conjugates of the transporters derived from HIV Tat and from Antennapedia. Moreover, R(7)-(psi)(epsilon)RACK conjugate reduced ischemic damage when delivered into intact hearts either prior to or after the ischemic insult.


CONCLUSIONS
Our data suggest that R(7) converts a peptide lead into a potential therapeutic agent for the ischemic heart.
Chen
L
L
Department of Molecular Pharmacology, Stanford University School of Medicine, Stanford, CA 94305-5174, USA.
Wright
L R
LR
Chen
C H
CH
Oliver
S F
SF
Wender
P A
PA
Mochly-Rosen
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D000818:Animals; D001692:Biological Transport; D002316:Cardiotonic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D004789:Enzyme Activation / Q000187:drug effects; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control; D009842:Oligopeptides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D010455:Peptides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D010539:Permeability; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051744:Protein Kinase C-epsilon; D051381:Rats; D017207:Rats, Sprague-Dawley
D002316:Cardiotonic Agents; D007527:Isoenzymes; D009842:Oligopeptides; D010455:Peptides; C015462:polyarginine; C497257:Prkce protein, rat; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon