Natriuretic peptide pathways in heart failure: further therapeutic possibilities

Abstract

The discovery of the heart as an endocrine organ resulted in a remarkable recognition of the natriuretic peptide system (NPS). Specifically, research has established the production of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) from the heart, which exert pleiotropic cardiovascular, endocrine, renal, and metabolic actions via the particulate guanylyl cyclase A receptor (GC-A) and the second messenger, cGMP. C-type natriuretic peptide (CNP) is produced in the endothelium and kidney and mediates important protective auto/paracrine actions via GC-B and cGMP. These actions, in part, participate in the efficacy of sacubitril/valsartan in heart failure (HF) due to the augmentation of the NPS. Here, we will review important insights into the biology of the NPS, the role of precision medicine, and focus on the phenotypes of human genetic variants of ANP and BNP in the general population and the relevance to HF. We will also provide an update of the existence of NP deficiency states, including in HF, which provide the rationale for further therapeutics for the NPS. Finally, we will review the field of peptide engineering and the development of novel designer NPs for the treatment of HF. Notably, the recent discovery of a first-in-class small molecule GC-A enhancer, which is orally deliverable, will be highlighted. These innovative designer NPs and small molecule possess enhanced and novel properties for the treatment of HF and cardiovascular diseases.

Keywords: Guanylyl cyclase drug discovery; Heart failure; Natriuretic peptides; Small molecules.

Graphical Abstract

Endocrine organs producing endogenous NPs, which activate GC receptors, include the heart, kidney, endothelium, and venomous glands of the green mamba snake. Specifically, ANP and BNP are produced in the heart and activate GC-A. URO is produced in the kidney and activates GC-A. CNP is produced in the kidney and endothelium and activates GC-B. DNP is produced in the venomous glands of the green mamba snake and activates GC-A. Designer NPs are enhanced engineered NPs which activate GC-A, GC-B, both GC-A/GC-B and GC-A/MasR. These designer NPs are being developed to target cardiorenal syndrome with acute kidney injury, post-acute HF, HFrEF, and HFpEF.

Figure 1

Amino acid structures of ANP, URO, BNP, DNP, CNP, and their respective receptor targets, GC-A and GC-B.

Figure 2

Organ and cell types in which NPs bind to GC-A or GC-B and activate the signalling pathways of cGMP. Once the intracellular concentration of cGMP increases, cGMP-gated cation channels, cGMP-dependent protein kinases, and phosophodiesterases generate important biological responses in different organs and cell types. GTP, guanosine triphosphate; PDEs, phosphodiesterases; PKGs, cGMP-dependent protein kinases G.

Figure 3

Specific biological properties of GC-A and GC-B.

Figure 4

Amino acid sequences of the designer natriuretic peptides cenderitide, ANX042 and MANP.

Figure 5

Orthosteric and positive allosteric modulation. NPs (square), such as ANP and BNP, would bind to the orthosteric site of GC-A inducing a conformational change that would lead to cGMP generation. GC-A-positive allosteric modulator (PAM), such as MCUF-651, would bind to topographically distinct site(s) on the receptor to increase the affinity and/or efficacy of orthosteric ligands to which enhances cGMP signalling.