Molecular transporters for peptides: delivery of a cardioprotective epsilonPKC agonist peptide into cells and intact ischemic heart using a transport system, R(7).

Abstract

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.

• Authors: L Chen, L R Wright, C H Chen, S F Oliver, P A Wender, D Mochly-Rosen
• Journal: Chemistry & biology (Chem Biol) Vol. 8 Issue 12 Pg. 1123-9 (Dec 2001) ISSN: 1074-5521 [Print] United States
• PMID: 11755391 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cardiotonic Agents
• Isoenzymes
• Oligopeptides
• Peptides
• polyarginine
• Prkce protein, rat
• Protein Kinase C
• Protein Kinase C-epsilon

Topics

• Animals
• Biological Transport
• Cardiotonic Agents (administration & dosage, pharmacokinetics)
• Drug Delivery Systems
• Enzyme Activation (drug effects)
• In Vitro Techniques
• Isoenzymes (antagonists & inhibitors, metabolism)
• Male
• Myocardial Ischemia (metabolism, prevention & control)
• Myocardial Reperfusion Injury (metabolism, prevention & control)
• Oligopeptides (administration & dosage, pharmacokinetics)
• Peptides (administration & dosage, pharmacokinetics)
• Permeability
• Protein Kinase C (antagonists & inhibitors, metabolism)
• Protein Kinase C-epsilon
• Rats
• Rats, Sprague-Dawley