Natriuretic Peptide-Based Novel Therapeutics: Long Journeys of Drug Developments Optimized for Disease States

SIMPLE SUMMARY: Natriuretic peptides are endogenous hormones produced in the heart and vascular endothelium, and they enable cardiorenal protective actions or bone growth via cGMP stimulation through their receptor guanylyl cyclase receptor A or B. To optimize the drug for each disease state, we must consider drug metabolism, delivery systems, and target receptor(s). This review summarizes attempts to develop novel natriuretic peptide-based therapeutics, including novel designer natriuretic peptides and oral drugs to enhance endogenous natriuretic peptides. We introduce some therapeutics that have been successful in clinical practice, as well as the prospective drug developments in the natriuretic peptide system for disease states. ABSTRACT: The field of natriuretic peptides (NPs) as an endocrine hormone has been developing since 1979. There are three peptides in humans: atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), which bind to the guanylyl cyclase-A (GC-A) receptor (also called natriuretic peptide receptor-A (NPR-A)), and C-type natriuretic peptide (CNP), which binds to the GC-B receptor (also called the NPR-B) and then synthesizes intracellular cGMP. GC-A receptor stimulation has natriuretic, vasodilatory, cardiorenal protective and anti-renin–angiotensin–aldosterone system actions, and GC-B receptor stimulation can suppress myocardial fibrosis and can activate bone growth before epiphyseal plate closure. These physiological effects are useful as therapeutics for some disease states, such as heart failure, hypertension, and dwarfism. To optimize the therapeutics for each disease state, we must consider drug metabolism, delivery systems, and target receptor(s). We review the cardiac NP system; new designer NPs, such as modified/combined NPs and modified peptides that can bind to not only NP receptors but receptors for other systems; and oral drugs that enhance endogenous NP activity. Finally, we discuss prospective drug discoveries and the development of novel NP therapeutics.