title: 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.
authors: Center for Arrhythmia Research, University of Michigan Medical School, 5025 Venture Dr, Ann Arbor MI 48104, USA.
authors: Vandana
authors: V
authors: Verma
authors: Bjarne Due
authors: BD
authors: Larsen
authors: Wanda
authors: W
authors: Coombs
authors: Xianming
authors: X
authors: Lin
authors: Gaelle
authors: G
authors: Spagnol
authors: Paul L
authors: PL
authors: Sorgen
authors: Steven M
authors: SM
authors: Taffet
authors: Mario
authors: M
authors: Delmar
mesh_terms: D000200:Action Potentials; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D000889:Anti-Arrhythmia Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D017076:Computer-Aided Design; D018031:Connexin 43 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015195:Drug Design; D017629:Gap Junctions / Q000187:drug effects* / Q000378:metabolism; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020349:Surface Plasmon Resonance; D013997:Time Factors; D014162:Transfection
chemical_list: D000889:Anti-Arrhythmia Agents; D018031:Connexin 43; C500216:GJA1 protein, human; D009842:Oligopeptides; D010456:Peptides, Cyclic