Novel pharmacophores of connexin43 based on the "rxp" series of Cx43-binding peptides

Vandana Verma, Bjarne Due Larsen, Wanda Coombs, Xianming Lin, Gaelle Spagnol, Paul L. Sorgen, Steven M. Taffet, Mario Delmar

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Gap junction pharmacology is a nascent field. Previous studies have identified molecules that enhance intercellular communication, and may offer potential for innovative antiarrhythmic therapy. However, their specific molecular target(s) and mechanism(s) of action remain unknown. Previously, we identified a 34-aa peptide (RXP-E) that binds the carboxyl terminal domain of C43 (Cx43CT) and prevents cardiac gap junction closure and action potential propagation block. These results supported the feasibility of a peptide-based pharmacology to Cx43, but the structure of the core active element in RXP-E, an essential step for pharmacological development, remained undefined. Here, we used a combination of molecular modeling, surface plasmon resonance, nuclear magnetic resonance and patch-clamp strategies to define, for the first time, a unique ensemble of pharmacophores that bind Cx43CT and prevent closure of Cx43 channels. Two particular molecules are best representatives of this family: a cyclized heptapeptide (called CyRP-71) and a linear octapeptide of sequence RRNYRRNY. These 2 small compounds offer the first structural platform for the design of Cx43-interacting gap junction openers. Moreover, the structure of these compounds offers an imprint of a region of Cx43CT that is fundamental to gap junction channel function.

Original languageEnglish (US)
Pages (from-to)176-184
Number of pages9
JournalCirculation Research
Volume105
Issue number2
DOIs
StatePublished - Jul 17 2009

Keywords

  • Arrhythmias
  • Connexin 43
  • Gap junctions

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Verma, V., Larsen, B. D., Coombs, W., Lin, X., Spagnol, G., Sorgen, P. L., Taffet, S. M., & Delmar, M. (2009). Novel pharmacophores of connexin43 based on the "rxp" series of Cx43-binding peptides. Circulation Research, 105(2), 176-184. https://doi.org/10.1161/CIRCRESAHA.109.200576