Design, Synthesis, and Actions of a Novel Chimeric Natriuretic Peptide: CD-NP

Lisý, Ondřej; Huntley, Brenda K.; McCormick, Daniel J.; Kurlansky, Paul; Burnett, John C.

doi:10.1016/j.jacc.2008.02.077

Cited by 168 publications

(191 citation statements)

References 44 publications

Supporting

Mentioning

185

Contrasting

Unclassified

Order By: Relevance

“…Furthermore, CD-NP increases the glomerular filtration rate (GFR) more than BNP (7). Although CD-NP infusion significantly increases cGMP concentrations in plasma, urine, and cultured fibroblasts, the ability of CD-NP to bind and activate each NPR was not determined.…”

mentioning

confidence: 99%

Novel Bifunctional Natriuretic Peptides as Potential Therapeutics

Dickey

Burnett

Potter

2008

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Synthetic atrial natriuretic peptide (carperitide) and B-type natriuretic peptide (BNP; nesiritide) are used to treat congestive heart failure. However, despite beneficial cardiac unloading properties, reductions in renal perfusion pressures limit their clinical effectiveness. Recently, CD-NP, a chimeric peptide composed of C-type natriuretic peptide (CNP) fused to the C-terminal tail of Dendroaspis natriuretic peptide (DNP), was shown to be more glomerular filtration rate-enhancing than BNP in dogs. However, the molecular basis for the increased responsiveness was not determined. Here, we show that the DNP tail has a striking effect on CNP, converting it from a nonagonist to a partial agonist of natriuretic peptide receptor (NPR)-A while maintaining the ability to activate NPR-B. This effect is specific for human receptors because CD-NP was only a slightly better activator of rat NPR-A due to the promiscuous nature of CNP in this species. Interesting, the DNP tail alone had no effect on any NPR even though it is effective in vivo. To further increase the potency of CD-NP for NPR-A, we converted two different triplet sequences within the CNP ring to their corresponding residues in BNP. Both variants demonstrated increased affinity and full agonist activity for NPR-A, whereas one was as potent as any NPR-A activator known. In contrast to a previous report, we found that DNP binds the natriuretic peptide clearance receptor (NPR-C). However, none of the chimeric peptides bound NPR-C with significantly higher affinity than endogenous ligands. We suggest that bifunctional chimeric peptides represent a new generation of natriuretic peptide therapeutics.The human natriuretic peptide system consists of atrial natriuretic peptide (ANP), 2 B-type natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and an N-terminally extended renal form of ANP called urodilatin (1). ANP, BNP, and urodilatin bind natriuretic peptide receptor (NPR)-A, whereas CNP binds NPR-B. Both receptors are transmembrane guanylyl cyclases, which when activated catalyze the synthesis of cGMP. The natriuretic peptide clearance receptor (NPR-C) lacks guanylyl cyclase activity and functions primarily to clear natriuretic peptides from the circulation. However, a signaling function has been proposed for this receptor as well (2).Both ANP and BNP reduce blood pressure by increasing natriuresis, diuresis, vasodilation, and endothelial permeability. They also prevent cardiac hypertrophy and suppress the reninangiotensin-aldosterone systems. In 2001, BNP was approved by the United States Food and Drug Administration for the treatment of acutely decompensated heart failure. However, recent reports have suggested impaired renal function, which may be related to excessive hypotension (3, 4).CD-NP represents a new class of natriuretic peptide drug that may circumvent the hypotensive nature of BNP and preserve or augment renal function in the congestive heart failure setting. CD-NP contains the full-length 22-amino acid human CNP fused to the 15-amino acid C...

show abstract

mentioning

confidence: 99%

Novel Bifunctional Natriuretic Peptides as Potential Therapeutics

Dickey

Burnett

Potter

2008

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…CD-NP is a designer natriuretic peptide consisting of the 15-residue carboxyl terminus of dendroaspis natriuretic peptide appended to the carboxyl terminus of CNP (Lisy et al, 2008) (Fig. 1).…”

Section: Discussionmentioning

confidence: 99%

Arg13 of B-Type Natriuretic Peptide Reciprocally Modulates Binding to Guanylyl Cyclase but Not Clearance Receptors

et al. 2010

View full text Add to dashboard Cite

B-type natriuretic peptide (BNP) decreases cardiac preload and hypertrophy. As such, synthetic BNP, nesiritide, was approved for the treatment of acutely decompensated heart failure. However, two problems limit its therapeutic potential. First, ensuing hypertension decreases urine output, and second, guanylyl cyclase-A (GC-A), the primary signaling receptor for BNP, is down-regulated in heart failure. Thus, alternative or chimeric natriuretic peptides maintaining the renal but lacking the vasorelaxation properties of BNP provide an alternative approach. Here, we examined the ability of single amino acid substitutions in the conserved 17-amino acid disulfide ring structure of human BNP to activate GC-A and guanylyl cyclase-B (GC-B), which is not reduced in heart failure. We hypothesized that substitution of highly conserved residues in BNP with highly conserved residues from a GC-B-specific peptide would yield BNP variants with increased and decreased potency for human GC-B and GC-A, respectively. Substitution of Leu for Arg13 (L-BNP) yielded a 5-fold more potent activator of GC-B and 7-fold less potent activator of GC-A compared with wild type. L-BNP also bound GC-A 4.5-fold less tightly than wild type. In contrast, substitution of Met for Ser21 (M-BNP) had no effect. A peptide containing both the Leu and Met substitutions behaved similarly to L-BNP. Meanwhile, wild-type and L-BNP bound the natriuretic peptide clearance receptor with similar affinities. These data indicate that Arg13 of BNP is a critical discriminator of binding to guanylyl cyclase-linked but not clearance natriuretic peptide receptors, supporting designer natriuretic peptides as an alternative to wild-type BNP for the treatment of heart failure.

show abstract

“…In order to obtain a more favorable hemodynamic profile several natriuretic peptide derivatives have been developed. The first chimeric natriuretic peptide (CD-NP) comprised the C-terminus of the dendroaspis peptide (derived from snake venom) and the peptide ring component of the cardiac-type natriuretic (CNP) [119]. CD-NP has been shown to have a potent natriuretic effect, antagonize the RAAS system, inhibit cardiac fibroblast proliferation and collagen synthesis, and importantly not cause significant systemic hypotension [120,121].…”

Section: Fibrosismentioning

confidence: 99%