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.