Novel Peptide Isomer Strategy for Stable Inhibition of Catecholamine Release
Application to Hypertension
Although hypertension remains the most potent and widespread cardiovascular risk factor, its pharmacological treatment has achieved only limited success. The chromogranin A–derived fragment catestatin inhibits catecholamine release by acting as an endogenous nicotinic cholinergic antagonist and can rescue hypertension in the setting of chromogranin A–targeted ablation. Here, we undertook novel peptide chemistry to synthesize isomers of catestatin: normal/wild-type as well as a retro-inverso (R-I) version, with not only inversion of chirality (L→D amino acids) but also reversal of sequence (carboxyl→amino). The R-I peptide was entirely resistant to proteolytic digestion and displayed enhanced potency as well as preserved specificity of action toward nicotinic cholinergic events: catecholamine secretion, agonist desensitization, secretory protein transcription, and cationic signal transduction. Structural modeling suggested similar side-chain orientations of the wild-type and R-I isomers, whereas circular dichroism spectroscopy documented inversion of chirality. In vivo, the R-I peptide rescued hypertension in 2 mouse models of the human trait: monogenic chromogranin A–targeted ablation, with prolonged efficacy of the R-I version and a polygenic model, with magnified efficacy of the R-I version. These results may have general implications for generation of metabolically stable mimics of biologically active peptides for cardiovascular pathways. The findings also point the way toward a potential new class of drug therapeutics for an important risk trait and, more generally, open the door to broader applications of the R-I strategy in other pathways involved in cardiovascular biology, with the potential for synthesis of diagnostic and therapeutic probes for both physiology and disease.
- Received July 13, 2012.
- Revision received August 2, 2012.
- Accepted September 6, 2012.
- © 2012 American Heart Association, Inc.