ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Cardiovascular and Smooth Muscle Pharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1692472
This article is part of the Research TopicNew Frontiers in Heart Failure Therapy: Mechanisms, Efficacy, and ChallengesView all 12 articles
A novel bioactive peptide-peptoid hybrid of alpha-calcitonin gene-related peptide protects against pressure-overload induced heart failure
Provisionally accepted
- University of South Carolina, Columbia, United States
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Background-Alpha-calcitonin gene-related peptide (α-CGRP) is a cardioprotective neuropeptide. However, due to low bioavailability, its use as a therapeutic agent is limited. The aim of the present study was to develop a stable and bioactive α-CGRP analog and to determine its cardioprotective effects in a mouse model of heart failure (HF). Methods-We chemically synthesized a peptide-peptoid hybrid: human α-CGRP containing two monomers of N-methoxy-ethyl glycine peptoid at the N-terminus (NMEG-CGRP). The toxicity, bioactivity, and stability of NMEG-CGRP were determined by MTT-cell viability assay, mouse blood pressure measurement, and in-vitro digestion with insulin degrading enzyme (IDE) followed by LC-MS, respectively. Male C57BL6 mice were underwent transverse aortic constriction (TAC) and were divided into: Sham, Sham+NMEG-CGRP, TAC, and TAC+NMEG-CGRP. Two-day post-TAC, NMEG-CGRP (3.6 mg/kg/mouse) was administered subcutaneously on alternate days, for a total of 28 days. Cardiac function was measured weekly using echocardiography. At the endpoint, mice were euthanized, and hearts were collected for analysis. Results-Our results demonstrated that NMEG-CGRP was non-toxic to rat H9C2 cells, more stable to IDE digestion, and bioactive. TAC-induced pressure-overload decreased ejection fraction and increased cardiac hypertrophy and dilation, fibrosis, apoptosis, oxidative stress, and macrophage infiltration in the left ventricles. NMEG-CGRP administration significantly attenuated these TAC-induced adverse cardiac effects in the HF mice. Conclusion-Together, our results demonstrated that NMEG-CGRP is a non-toxic, stable, and bioactive CGRP-analog, and protects against pressure-induced HF in mice. Thus, NMEG-CGRP is a promising novel CGRP-analog that may be used in the treatment of HF and potentially other cardiac diseases.
Keywords: Cardioprotection, Cardiovascular Diseases, CGRP agonist analog, Heart Failure, Peptide-peptoidhybrid, Therapeutic agent, Vasodilator, NMEG
Received: 25 Aug 2025; Accepted: 22 Oct 2025.
Copyright: © 2025 Potts, Kumar, Deloach and DiPette. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jay Potts, jay.potts@uscmed.sc.edu
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