1. Natriuretic peptide based therapeutics for heart failure: Cenderitide: A novel first-in-class designer natriuretic peptide
John C Burnett Jr, Nina Dzhoyashvili, Tomoko Ichiki Int J Cardiol . 2019 Apr 15;281:166-171. doi: 10.1016/j.ijcard.2018.06.002.
Cenderitide is a novel designer natriuretic peptide (NP) composed of C-type natriuretic peptide (CNP) fused to the C-terminus of Dendroaspis natriuretic peptide (DNP). Cenderitide was engineered to co-activate the two NP receptors, particulate guanylyl cyclase (pGC)-A and pGC-B. The rationale for its design was to achieve the renal-enhancing and anti-fibrotic properties of dual receptor activation, but without clinically significant hypotension. Here, we review the biology of the NPs and the rationale for their use in heart failure. Most importantly, we present the key studies related to the discovery of Cenderitide. Finally, we review the key clinical studies that have advanced this first-in-class dual NP receptor activator for heart failure.
2. Dendroaspis natriuretic peptide relaxes isolated human arteries and veins
Amir Lerman, Stephanie H Wilson, John C Burnett, David R Holmes Jr, Patricia J M Best Cardiovasc Res . 2002 Aug 1;55(2):375-84. doi: 10.1016/s0008-6363(02)00402-9.
Background:Dendroaspis natriuretic peptide (DNP) is the newest member of the natriuretic peptide family and is a circulating peptide in humans. The effects of DNP on the human vasculature are unknown. Since other natriuretic peptides are known to cause vasorelaxation, we determined the response to DNP on human blood vessels in vitro. We also investigated the mechanism of DNP mediated vasorelaxation.Methods:Rings of human internal mammary artery and saphenous vein were suspended in an organ bath. The response to cumulative concentrations of DNP was obtained. Inhibiting agents were used to determine the mechanism of this vasorelaxation.Results:DNP caused dose-dependent relaxation, with a greater effect on the internal mammary arteries (relaxation from 10(-7) mol/l DNP: 80.6+/-4.1%) than the saphenous veins (33.4+/-4.1%). At 10(-7) mol/l, DNP resulted in less arterial relaxation compared with atrial and C-type natriuretic peptides and similar relaxation to brain natriuretic peptide. In veins, DNP caused the greatest relaxation of the natriuretic peptides. DNP increased tissue cyclic guanosine monophosphate (cGMP) determined by radioimmunoassay by over 7-fold. Barium chloride and indomethacin attenuated DNP mediated vasorelaxation. However, glibenclamide, charydotoxin, apamin, tetraethyl-ammonium chloride and diisothiocyanato-stilbene-2,2'-disulfonic acid did not. DNP mediated vasorelaxation was mildly attenuated with removal of the endothelium. DNP immunoreactivity was identified in both arteries and veins.Conclusions:The current study demonstrates that DNP is an endogenous human natriuretic peptide that relaxes human arteries more than veins. Furthermore, DNP mediated vasorelaxation involves the inward rectifying potassium channels, prostaglandins, and cGMP. This newest member of the natriuretic peptide family may have an important physiologic role in the human vasculature.
3. Natriuretic peptide drug leads from snake venom
A H Jin, S Vink, P F Alewood, K J Poth, G A Head Toxicon . 2012 Mar 15;59(4):434-45. doi: 10.1016/j.toxicon.2010.12.001.
Natriuretic peptides are body fluid volume modulators, termed natriuretic peptides due to a role in natriuresis and diuresis. The three mammalian NPs, atrial natriuretic peptide (ANP), brain or b-type natriuretic peptide (BNP) and c-type natriuretic peptide (CNP), have been extensively investigated for their use as therapeutic agents for the treatment of cardiovascular diseases. Although effective, short half-lives and renal side effects limit their use. In approximately 30 years of research, NPs have been discovered in many vertebrates including mammals, amphibians, reptiles and fish, with plants and, more recently, bacteria also being found to possess NPs. Reptiles have produced some of the more interesting NPs, with dendroaspis natriuretic peptide (DNP), which was isolated from the venom of the green mamba (Dendroaspis angusticeps), having greater potency and increased stability as compared to the mammalian family members, and taipan natriuretic peptide c (TNPc), which was isolated from the venom of the inland taipan (Oxyuranus microlepidotus) displaying similar activity to ANP and DNP at rat natriuretic peptide receptor A. Although promising, more research is required in this field to develop therapeutics that overcome receptor-mediated clearance, and potential toxicity issues. This review investigates the use of snake venom NPs as therapeutic drug leads.
