Natriuretic Peptides as the Basis of Peptide Drug Discovery for Cardiovascular Diseases.

Cardiovascular diseases (CVDs) are the leading global cause of death, accounting for more than 17.6 million deaths per year in 2016, a number that is expected to grow to more than 23.6 million by 2030. While many technologies are currently under investigation to improve the therapeutic outcome of CVD complications, only a few medications have been approved. Therefore, new approaches to treat CVD are urgently required. Peptides regulate numerous physiological processes, mainly by binding to specific receptors and inducing a series of signals, neurotransmissions or the release of growth factors. Importantly, peptides have also been shown to play an important role in the circulatory system both in physiological and pathological conditions. Peptides, such as angiotensin II, endothelin, urotensin-II, urocortins, adrenomedullin and natriuretic peptides have been implicated in the control of vascular tone and blood pressure as well as in CVDs such as congestive heart failure, atherosclerosis, coronary artery disease, and pulmonary and systemic hypertension. Hence it is not surprising that peptides are becoming important therapeutic leads in CVDs. This article will review the current knowledge on peptides and their role in the circulatory system, focusing on the physiological roles of natriuretic peptides in the cardiovascular system and their implications in CVDs.

Liquid-Phase Total Synthesis of Plecanatide Aided by Diphenylphosphinyloxyl Diphenyl Ketone (DDK) Derivatives.

Plecanatide is an oral guanylate cyclase-C agonist for the treatment of gastrointestinal disorders. The large-scale supply of plecanatide is restrained primarily by its industrial manufacture. Herein we developed diphenylphosphinyloxyl diphenyl ketone (DDK) derivatives as greener supports with unique precipitation-inducing properties to aid the liquid-phase total synthesis of plecanatide without the use of chromatography. Plecanatide could be obtained in high yield, and the ultimately sheared DDK derivative residue could be directly recycled or regenerated for reuse.

Long-term blood pressure lowering and cGMP-activating actions of the novel ANP analog MANP.

Based on the cardiac hormone atrial natriuretic peptide (ANP) and its seminal role in blood pressure (BP) homeostasis, we investigated the chronic BP lowering actions of a novel ANP analog currently entering clinical trials for hypertension. Previous reports demonstrate that this analog MANP activates the guanylyl cyclase A receptor (GC-A) and results in more potent biological actions compared with ANP; thus, it may represent a new therapeutic drug for hypertension. A major goal of this study was to establish that chronic subcutaneous delivery of MANP is feasible and hypotensive together with cGMP effects. We investigated the BP-lowering and cGMP-activating actions of acute and chronic subcutaneous delivery in normal and hypertensive rats. Furthermore, we explored vascular mechanisms of MANP in human aortic smooth muscle cells (HASMC) and ex vivo in isolated arteries. In normal rats with a single subcutaneous injection, MANP promoted robust dose-dependent BP-lowering actions and natriuresis, together with cGMP activation. Most importantly in hypertensive rats, once-a-day subcutaneous injection of MANP for 7 days induced cGMP elevation and long-term BP reduction compared with vehicle. Mechanistically, in HASMC, MANP activated cGMP and attenuated angiotensin II-mediated increases in intracellular Ca2+ levels while directly vasorelaxing arterial rings. Our study demonstrates for the first time the effectiveness of subcutaneous administration of MANP for 7 days and provides innovative, vascular mechanisms of BP regulation supporting its continued development as a novel therapeutic for hypertension.

A defined α-helix in the bifunctional O-glycosylated natriuretic peptide TcNPa from the venom of Tropidechis carinatus.

Natriuretic peptides (NP) play important roles in human cardiac physiology through their guanylyl cyclase receptors NPR-A and NPR-B. Described herein is a bifunctional O-glycosylated natriuretic peptide, TcNPa, from Tropidechis carinatus venom and it unusually targets both NPR-A and NPR-B. Characterization using specific glycosidases and ETD-MS identified the glycan as galactosyl-ß(1-3)-N-acetylgalactosamine (Gal-GalNAc) and was α-linked to the C-terminal threonine residue. TcNPa contains the characteristic NP 17-membered disulfide ring with conserved phenylalanine and arginine residues. Both glycosylated and nonglycosylated forms were synthesized by Fmoc solid-phase peptide synthesis and NMR analysis identified an α-helix within the disulfide ring containing the putative pharmacophore for NPR-A. Surprisingly, both forms activated NPR-A and NPR-B and were relatively resistant towards proteolytic degradation in plasma. This work will underpin the future development of bifunctional NP peptide mimetics.