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.
Highlights
Connexin43-Formed ChannelsThe subunit of gap junction channels, connexin proteins, are widely expressed in the heart, as well as throughout the body [1,2,3,4]
Fralin Biomedical Research Institute at VTC, Virginia Tech, Roanoke, VA 24016, USA; Center for Heart and Reparative Medicine Research, Virginia Tech, Roanoke, VA 24016, USA
Over the last decade, there has been growing interest in the potential for connexin pharmacology. This has occurred as a result of growing evidence of roles for connexin-formed channels in clinically relevant phenomena including arrhythmias, cancer, wound healing, inflammation, and tissue injury responses, as well as the growing understanding of the potential contribution of HCs and gap junction (GJ) to the “bystander effect”, such as what occurs in myocardium-at-risk following myocardial infarction (MI)
Summary
The subunit of gap junction channels, connexin proteins, are widely expressed in the heart, as well as throughout the body [1,2,3,4]. A focus of this review is the biology and pathophysiology of HCs formed formed by Cx43 in the myocardium, as well as the growing literature on the opportunities by Cx43 in the myocardium, as well as the growing literature on the opportunities and and barriers to pharmacological targeting of these channels in the treatment of heart disease. There is a wealth of preclinical data indicating the potential for therapeutic benefit from targeting HC activity by drugs mimicking the sequence of Cx43 in experimental models of targeting HC activity by drugs mimicking the sequence of Cx43 in experimental models human pathology, including those involving injury to the skin, heart, and brain [4,25,26,27,28,29]. If translation of these Cx43-targeting drugs to the clinic is to occur, careful attention to addressing questions of how to safely and effectively deliver drugs based on short peptides is required
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
