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
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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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