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

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 Cx43 (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.

journal_name

Circ Res

journal_title

Circulation research

authors

Verma V,Larsen BD,Coombs W,Lin X,Spagnol G,Sorgen PL,Taffet SM,Delmar M

doi

10.1161/CIRCRESAHA.109.200576

subject

Has Abstract

pub_date

2009-07-17 00:00:00

pages

176-84

issue

2

eissn

0009-7330

issn

1524-4571

pii

CIRCRESAHA.109.200576

journal_volume

105

pub_type

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