Design, synthesis, and actions of a novel chimeric natriuretic peptide: CD-NP.
OBJECTIVE
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.
Lisy
Ondrej
O
Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic and Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. lisy.ondrej@mayo.edu
Huntley
Brenda K
BK
McCormick
Daniel J
DJ
Kurlansky
Paul A
PA
Burnett
John C
JC
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure; D049109:Cell Proliferation; D002678:Chimera; D006152:Cyclic GMP / Q000378:metabolism; D004232:Diuretics / Q000494:pharmacology*; D004285:Dogs; D015195:Drug Design; D004546:Elapid Venoms; D005347:Fibroblasts; D005919:Glomerular Filtration Rate; D006321:Heart / Q000187:drug effects; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D006439:Hemodynamics; D006801:Humans; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins; D007668:Kidney / Q000187:drug effects; D009206:Myocardium / Q000166:cytology; D020098:Natriuretic Peptide, C-Type; D010455:Peptides; D012083:Renin / Q000187:drug effects
D000959:Antihypertensive Agents; C075597:Dendroaspis natriuretic peptide; D004232:Diuretics; D004546:Elapid Venoms; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D020098:Natriuretic Peptide, C-Type; D012083:Renin; D006152:Cyclic GMP