Abstract
C-type natriuretic peptide (CNP) is a pluripotent molecule produced by the endothelium and myocardium with therapeutic potential in pulmonary hypertension, myocardial infarction, and heart failure. However, the native peptide’s short elimination half-life of under 3 minutes limits its use clinically. To improve the pharmacokinetic profile of CNP we recombinantly expressed the CNP peptide as a fusion with an elastin-like polypeptide (ELP). ELPs are biopolymers that undergo reversible temperature-dependent phase separation and form a subcutaneous depot upon injection. CNP-ELP fusion proteins were expressed in E. coli , purified, and showed in vitro potency 2-4 fold less than native CNP. When administered subcutaneously in mice CNP-ELP showed a significantly enhanced PK profile due to the slow release of the fusion into the circulation with detectable fusion protein 24 hours after a single injection. In addition, the CNP-ELP increased growth velocity in mice significantly greater than that of native peptide indicating an in vivo activation of the CNP receptor, NPR-B. These findings represent a new method of administering a long acting CNP peptide for treatment of different cardiovascular diseases.
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