Designer Natriuretic Peptides for Heart Failure

Abstract

The endogenous natriuretic peptides ANP, BNP and CNP, via particulate guanylyl cyclase (GC) receptors and the second messenger cyclic guanosine monophosphate (cGMP), are potent activators of key signaling pathways. Emerging research suggests that in human disease such as heart failure (HF) these natriuretic peptides (NP), which possess broad pleiotropic protective properties, may be deficient or may be released by the heart as abnormal molecular forms with reduced pGC activating properties. Therefore, novel NP/GC/cGMP therapies and innovative NP peptide delivery systems are being developed. CD-NP (cenderitide) represents a new class of NP, which we call designer NPs which was designed at Mayo Clinic. CD-NP represents the most clinically advanced of the designer NPs that is now in clinical trials for HF. CD-NP was uniquely designed to co-activate both the GC-A receptor to which ANP and BNP bind as well as GC-B to which CNP binds. Thus it has the unique ability to optimally activate the entire NP/GC receptor family. Clinical trials are now underway to chronically deliver CD-NP by a subcutaneous patch pump simulating the strategy for chronic insulin administration to reduce rehospitalization for HF. Other innovative delivery systems also include oral delivery and gene delivery. As increasing evidence supports the key role of hypertension especially resistant hypertension as a cause of HF, we also will discuss our second designer NP which is named MANP which functions as a super ANP and a pure GC-A agonist. Motivated by genetic studies that human hypertension may be linked in part to an ANP deficiency; MANP serves as a potent natriuretic, aldosterone suppressing and blood pressure lowering peptide, which goes beyond native ANP. Importantly, it may be delivered chronically both by subcutaneous, oral and novel nanotechnologies permitting enhanced hypertension control, which goes beyond conventional anti-hypertensive agents. Thus, designer NPs hold the promise as novel treatments as well as preventive strategies for HF resulting in a reduction in the burden of cardiovascular disease.