title: Novel peptide isomer strategy for stable inhibition of catecholamine release: application to hypertension.
abstract: 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.
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Nilima
authors.initials: N
authors.lastname: Biswas
authors.forename: Jiaur
authors.initials: J
authors.lastname: Gayen
authors.forename: Manjula
authors.initials: M
authors.lastname: Mahata
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Mahata
authors.forename: Daniel T
authors.initials: DT
authors.lastname: O'Connor
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D053379:Chromogranin A / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy*; D051379:Mice; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D053379:Chromogranin A; D010446:Peptide Fragments; C109084:chromogranin A (344-364)