Since the discovery of atrial natriuretic factor by de Bold et al., there has been tremendous progress in our understanding of the physiologic, diagnostic and therapeutic roles of the natriuretic peptides (NPs) in health and disease. Natriuretic peptides are endogenous hormones that are released by the heart in response to myocardial stretch and overload. Three mammalian NPs have been identified and characterized, including atrial natriuretic peptide (ANP or atrial natriuretic factor), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). In addition, Dendroaspis natriuretic peptide (DNP) has been isolated from the venom of Dendroaspis angusticeps (the green mamba snake), and urodilatin from human urine. These peptides are structurally similar and they consist of a 17-amino-acid core ring and a cysteine bridge. Both ANP and BNP bind to natriuretic peptide receptor A (NPR-A) that are expressed in the heart and other organs. Activation of NPR-A generates an increase in cyclic guanosine monophosphate, which mediates natriuresis, inhibition of renin and aldosterone, as well as vasorelaxant, anti-fibrotic, anti-hypertrophic, and lusitropic effects. The NP system thus serves as an important compensatory mechanism against neurohumoral activation in heart failure. This provides a strong rationale for the use of exogenous NPs in the management of acutely decompensated heart failure. In this article, the therapeutic applications of NPs in the acute heart failure syndromes are reviewed. Emerging therapeutic agents and areas for future research are discussed.

CD-NP is a novel chimeric natriuretic peptide (NP) consisting of the 22-amino-acid (AA) human C-type natriuretic peptide (CNP), a venodilating peptide with limited renal actions and minimal effects on blood pressure, and the 15-AA C-terminus of Dendroaspis NP (DNP). The rationale for the design of CD-NP was to enhance the renal actions of CNP, the ligand for natriuretic peptide receptor-B, but without inducing excessive hypotension. Here we report the first-in-human studies for CD-NP, which represent the first successful clinical testing of a chimeric NP demonstrating in normal human volunteers that CD-NP possesses cyclic guanosine monophosphate-activating, natriuretic, and aldosterone-suppressing properties without inducing excessive hypotension, laying the foundation for additional studies on this first-in-class new cardiovascular therapeutic in human heart failure, which are now underway worldwide. KeywordsChimeric natriuretic peptide; CD-NP; C-type natriuretic peptide; Dendroaspis natriuretic peptide The design of novel chimeric peptides that are engineered to enhance the favorable properties of native peptides and delete or minimize unfavorable biological actions is an emerging therapeutic strategy in drug discovery.1 , 2 The novel chimeric natriuretic peptide, CD-NP,3 is being developed for the treatment of acute heart failure (AHF); there is a tremendous unmet need for therapy for this rapidly increasing cardiovascular syndrome, which has poor outcomes, and new drugs have repeatedly failed in clinical development.4 CD-NP represents the fusion of the 22-amino-acid (AA) human C-type natriuretic peptide (CNP) with the 15-AA C-terminus of Dendroaspis natriuretic peptide (DNP) (Figure 1).3 The rationale for its design was based on our knowledge that CNP,5 an endothelial6 , 7 cellderived peptide, which mediates favorable cardiovascular hemodynamic effects via the natriuretic peptide receptor (NPR)-B and the second messenger cyclic guanosine monophosphate (cGMP), unloads the heart without inducing excessive hypotension.8 These cardiovascular properties are based on the previous demonstration that CNP primarily

Aim Cenderitide is a novel dual natriuretic peptide (NP) receptor chimeric peptide activator, which targets the particulate guanylyl cyclase B (pGC-B) receptor and pGC-A unlike native NPs. Cenderitide was engineered to retain the anti-fibrotic properties of CNP/pGC-B with renal enhancing actions facilitated by fusion to the carboxyl-terminus of Dendroaspis NP (DNP), a pGC-A agonist, to CNP. Here, we address significance of the DNP carboxyl-terminus in dual pGC receptor activation and actions of cenderitide compared to CNP on renal function and cGMP in vivo and ex vivo in normal canines. Methods and Results In vitro, only cenderitide and not CNP or three CNP-based variants was a potent dual pGC-A/pGC-B activator of cGMP production (from 5 to 237 pmol/ml) in HEK293 cells overexpressing human pGC-A while in pGC-B overexpressing cells cenderitide increased cGMP production (from 4 to 321 pmol/ml) while the three CNP-based variants were weak agonists. Based upon our finding that the DNP carboxyl-terminus is a key structural requirement for dual pGC-A/pGC-B activation, we defined in vivo the renal enhancing actions of cenderitide compared to CNP. Cenderitide increased urinary cGMP excretion (from 989 to 5977 pmol/ml), net generation of renal cGMP (821 to 4124 pmol/min), natriuresis (12 to 242 ueq/min) and GFR (37 to 51 ml/min) while CNP did not. We then demonstrated the transformation of CNP ex vivo into a renal cGMP activating peptide which increased cGMP in freshly isolated glomeruli 8 fold greater than CNP. Conclusion The current study establishes that dual pGC-A and pGC-B activation with CNP requires the specific carboxyl-terminus of DNP. In normal canines in vivo and in glomeruli ex vivo, the carboxyl-terminus of DNP transforms CNP into a natriuretic and GFR enhancing peptide. Future studies of cenderitide are warranted in cardiorenal disease states to explore its efficacy in overall cardiorenal homeostasis.

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 -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 report the first clinical trial on the safety, tolerability and cyclic guanosine monophosphate (cGMP) activating properties of Cenderitide in subjects with stable HF. Four-hour infusion of Cenderitide was safe, well-tolerated and significantly increased plasma cGMP levels and urinary cGMP excretion without adverse effects with no change in blood pressure. Thus, Cenderitide has a favorable safety profile and expected pharmacological effects in stable human HF. Our results support further investigations of Cenderitide in HF as a potential future cGMP enhancing therapeutic strategy.

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