Design and characterization of the first peptidomimetic molecule that prevents acidification-induced closure of cardiac gap junctions.
BACKGROUND
Gap junctions are potential targets for pharmacologic intervention. We previously developed a series of peptide sequences that prevent closure of connexin43 (Cx43) channels, bind to cardiac Cx43, and prevent acidification-induced uncoupling of cardiac gap junctions.


OBJECTIVE
The purpose of this study was to identify and validate the minimum core active structure in peptides containing an RR-N/Q-Y motif. Based on that information, we sought to generate a peptidomimetic molecule that acts on the chemical regulation of Cx43 channels.


METHODS
Experiments were based on a combination of biochemical, spectroscopic, and electrophysiologic techniques as well as molecular modeling of active pharmacophores with Cx43 activity.


RESULTS
Molecular modeling analysis indicated that the functional elements of the side chains in the motif RRXY form a triangular structure. Experimental data revealed that compounds containing such a structure bind to Cx43 and prevent Cx43 chemical gating. These results provided us with the first platform for drug design targeted to the carboxyl terminal of Cx43. Using that platform, we designed and validated a peptidomimetic compound (ZP2519; molecular weight 619 Da) that prevented octanol-induced uncoupling of Cx43 channels and pH gating of cardiac gap junctions.


CONCLUSIONS
Structure-based drug design can be applied to the development of pharmacophores that act directly on Cx43. Small molecules containing these pharmacophores can serve as tools to determine the role of gap junction regulation in the control of cardiac rhythm. Future studies will determine whether these compounds can function as pharmacologic agents for the treatment of a selected subset of cardiac arrhythmias.
Verma
Vandana
V
Center for Arrhythmia Research, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48104, USA.
Larsen
Bjarne Due
BD
Coombs
Wanda
W
Lin
Xianming
X
Sarrou
Eliana
E
Taffet
Steven M
SM
Delmar
Mario
M
D000818:Animals; D002352:Carrier Proteins / Q000494:pharmacology; D002478:Cells, Cultured; D018031:Connexin 43 / Q000187:drug effects / Q000378:metabolism*; D015195:Drug Design; D017629:Gap Junctions / Q000187:drug effects* / Q000502:physiology; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008958:Models, Molecular; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology; D000442:Octanols / Q000494:pharmacology; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats
D002352:Carrier Proteins; D018031:Connexin 43; D000442:Octanols; D009842:Oligopeptides; D057786:Peptidomimetics; C532149:RXP-E peptide; C555342:ZP 2519