MANP: A novel designer natriuretic peptide GC-A activator for the treatment of hypertension and heart failure

Human arterial hypertension is the most frequent risk factor in the world for cardiovascular disease associated with increased mortality and morbidity. Atrial Natriuretic Peptide (ANP) is a hormone produced by the cardiac atria and has a pivotal role in the regulation of the cardiovascular system and body fluid homeostasis. Its well-known vasomodulatory properties and renin-angiotensin-aldosterone system (RAAS) counteractions, conferred by binding to the Guanylyl Cyclase A Receptor (CG-A) producing the second messenger cyclic GMP) make it a robust therapeutic agent for heart failure and hypertension. Currently, ANP is administered for treatment of HF by continuous intravenous infusion due to short half-life, the main limiting factor for its chronic use. Recently studies have defined a metabolic role of ANP beyond its blood pressure-lowering, natriuretic- and aldosterone-inhibiting properties, such that the ANP gene polymorphism rs5068 is associated with a low cardiovascular risk profile with protection from metabolic syndrome. Further physiological studies established that the gut peptide Glucagon-like Protein 1 (GLP-1) can stimulate the release of ANP from the atria also resulting in cardiorenal protection. Based upon these cardiorenal, humoral and metabolic properties of ANP, we engineered Mutant ANP (MANP) which represents a new and novel ANP-based peptide therapeutic consisting of 40 amino acids where the unique long C-terminus confers to the peptide a greater resistance to degradation than its native form. Indeed, in vitro studies demonstrated fewer sites for degradation and a greater cGMP production than ANP. In vivo studies showed sustained cardiorenal actions with enhanced vasorelaxation not only in normal canines but also in experimental acute hypertension and in hypertensive acute heart failure. In summary, for these reasons, MANP represents a new therapeutic agent for the treatment of chronic and resistant hypertension that is now entering human clinical trials.