Peptidic Connexin43 Therapeutics in Cardiac Reparative Medicine

Abstract

Connexin (Cx43)-formed channels have been linked to cardiac arrhythmias and diseases of the heart associated with myocardial tissue loss and fibrosis. These pathologies include ischemic heart disease, ischemia-reperfusion injury, heart failure, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, and Duchenne muscular dystrophy. A number of Cx43 mimetic peptides have been reported as therapeutic candidates for targeting disease processes linked to Cx43, including some that have advanced to clinical testing in humans. These peptides include Cx43 sequences based on the extracellular loop domains (e.g., Gap26, Gap 27, and Peptide5), cytoplasmic-loop domain (Gap19 and L2), and cytoplasmic carboxyl-terminal domain (e.g., JM2, Cx43tat, CycliCX, and the alphaCT family of peptides) of this transmembrane protein. Additionally, RYYN peptides binding to the Cx43 carboxyl-terminus have been described. In this review, we survey preclinical and clinical data available on short mimetic peptides based on, or directly targeting, Cx43, with focus on their potential for treating heart disease. We also discuss problems that have caused reluctance within the pharmaceutical industry to translate peptidic therapeutics to the clinic, even when supporting preclinical data is strong. These issues include those associated with the administration, stability in vivo, and tissue penetration of peptide-based therapeutics. Finally, we discuss novel drug delivery technologies including nanoparticles, exosomes, and other nanovesicular carriers that could transform the clinical and commercial viability of Cx43-targeting peptides in treatment of heart disease, stroke, cancer, and other indications requiring oral or parenteral administration. Some of these newly emerging approaches to drug delivery may provide a path to overcoming pitfalls associated with the drugging of peptide therapeutics.

Connexons Coupling to Gap Junction Channel: Potential Role for Extracellular Protein Stabilization Centers

“…Despite valuable insights into the structure and regulation of Cx HCs and GJCs [ 1 , 3 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ], one may have the impression that matters arising from the lack of Cx subtype-specific inhibitors and pertinent structural issues stayed somewhat unexplored [ 58 , 59 ].…”

The Cx43 Carboxyl-Terminal Mimetic Peptide αCT1 Protects Endothelial Barrier Function in a ZO1 Binding-Competent Manner

“…The shared myocardial protective effect of αCT1 and αCT1-I occurs independent of ZO1 interaction, and is correlated with negatively charged sequences common to both peptides, which mediate binding to the H2 domain of Cx43 [33]. The severity of heart IR injuries is thought in part to be determined by levels of activation of myocardial Cx43 hemichannels [46,47] and we have previously proposed that reductions in channel activity associated with targeting the Cx43 H2 domain (a short α-helical sequence within the Cx43 CT) [41] could account for the cardioprotective effects elicited by αCT1 and αCT1-I. [33].…”

New Insights into Pulmonary Hypertension: A Role for Connexin-Mediated Signalling

“…Currently, there are no published studies assessing the effects of the pharmacological targeting of connexins on the development of PH in animal models. However, much research is currently ongoing to improve the administration and the bioavailability of these drugs, for example, using exosomes as vehicles for peptide delivery [ 70 ]. Indeed, connexin mimetic peptides and analogues thereof are receiving increased attention in translational research in areas related to cardiovascular disease, cancer, neurological disorders and wound healing [ 71 ].…”