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

Ondrej Lisy, MD, PhD^_*,_*, Brenda K. Huntley^_*, Daniel J. McCormick, PhD, Paul A. Kurlansky, MD and John C. Burnett, Jr, MD^_*

^_* Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic and Mayo Clinic College of Medicine, Rochester, Minnesota
Laboratory of Expression Proteomics and Protein Chemistry, Mayo Clinic and Mayo Clinic College of Medicine, Rochester, Minnesota
Miami Heart Research Institute, Miami, Florida.

Manuscript received December 27, 2007; revised manuscript received February 19, 2008, accepted February 26, 2008.

^_* Reprint requests and correspondence: Dr. Ondrej Lisy, Cardiorenal Research Laboratory, Guggenheim 9, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905. (Email: lisy.ondrej{at}mayo.edu).

Objectives: Our aim was to design, synthesize and test in vivo and in vitro a new chimeric peptide that would combine the beneficial properties of 2 distinct natriuretic peptides with a biological profile that goes beyond native peptides.

Background: Studies have established the beneficial vascular and antiproliferative properties of C-type natriuretic peptide (CNP). While lacking renal actions, CNP is less hypotensive than the cardiac peptides atrial natriuretic peptide and B-type natriuretic peptide but unloads the heart due to venodilation. Dendroaspis natriuretic peptide is a potent natriuretic and diuretic peptide that is markedly hypotensive and functions via a separate guanylyl cyclase receptor compared with CNP.

Methods: Here we engineered a novel chimeric peptide CD-NP that represents the fusion of the 22-amino acid peptide CNP together with the 15-amino acid linear C-terminus of Dendroaspis natriuretic peptide. We also determined in vitro in cardiac fibroblasts cyclic guanosine monophosphate-activating and antiproliferative properties of CD-NP.

Results: Our studies demonstrate in vivo that CD-NP is natriuretic and diuretic, glomerular filtration rate enhancing, cardiac unloading, and renin inhibiting. CD-NP also demonstrates less hypotensive properties when compared with B-type natriuretic peptide. In addition, CD-NP in vitro activates cyclic guanosine monophosphate and inhibits cardiac fibroblast proliferation.

Conclusions: The current findings advance an innovative design strategy in natriuretic peptide drug discovery and development to create therapeutic peptides with favorable properties that may be preferable to those associated with native natriuretic peptides.

Key Words: peptide • kidney • blood pressure • cGMP • sodium excretion • fibroblasts

Abbreviations and Acronyms   AA = amino acid   AHF = acute heart failure   AMI = acute myocardial infarction   ANP = atrial natriuretic peptide   BNP = B-type natriuretic peptide   BrdU = bromodeoxyuridine   CF = cardiac fibroblast   cGMP = cyclic 3'5' guanosine monophosphate   CNP = C-type natriuretic peptide   DNP = Dendroaspis natriuretic peptide   GFR = glomerular filtration rate   NEP = neutral endopeptidase   NMP = 1-methyl-2-pyrrolidinone   PFRNa = proximal fractional sodium reabsorption   PRA = plasma renin activity

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