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Review

Peptidic Connexin43 Therapeutics in Cardiac Reparative Medicine

1
Fralin Biomedical Research Institute at VTC, Virginia Tech, Roanoke, VA 24016, USA
2
Center for Heart and Reparative Medicine Research, Virginia Tech, Roanoke, VA 24016, USA
3
Translational Biology Medicine and Health Graduate Program, Virginia Tech, Roanoke, VA 24016, USA
4
Department of Biomedical Engineering and Mechanics, Virginia Tech, Blacksburg, VA 24061, USA
5
Department of Emergency Medicine, Virginia Tech Carilion School of Medicine, Virginia Tech, Roanoke, VA 24016, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Andy Wessels
J. Cardiovasc. Dev. Dis. 2021, 8(5), 52; https://doi.org/10.3390/jcdd8050052
Received: 2 March 2021 / Revised: 19 April 2021 / Accepted: 1 May 2021 / Published: 5 May 2021
(This article belongs to the Special Issue Cardiomyopathy at the Sub-Cellular Level)
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. View Full-Text
Keywords: connexin43; peptide; cardiac disease; cardiac therapeutic; drug delivery connexin43; peptide; cardiac disease; cardiac therapeutic; drug delivery
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MDPI and ACS Style

Marsh, S.R.; Williams, Z.J.; Pridham, K.J.; Gourdie, R.G. Peptidic Connexin43 Therapeutics in Cardiac Reparative Medicine. J. Cardiovasc. Dev. Dis. 2021, 8, 52. https://doi.org/10.3390/jcdd8050052

AMA Style

Marsh SR, Williams ZJ, Pridham KJ, Gourdie RG. Peptidic Connexin43 Therapeutics in Cardiac Reparative Medicine. Journal of Cardiovascular Development and Disease. 2021; 8(5):52. https://doi.org/10.3390/jcdd8050052

Chicago/Turabian Style

Marsh, Spencer R., Zachary J. Williams, Kevin J. Pridham, and Robert G. Gourdie 2021. "Peptidic Connexin43 Therapeutics in Cardiac Reparative Medicine" Journal of Cardiovascular Development and Disease 8, no. 5: 52. https://doi.org/10.3390/jcdd8050052

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