TDT: a highly potent and stable chimeric natriuretic peptide for heart failure treatment

Natriuretic peptides (NPs) are body fluid volume modulators that have implications in the treatment and management of several conditions, including heart failure, chronic respiratory disease and renal dysfunction. Congestive heart failure is a major burden for the health system; thus, improved therapeutics for the treatment of this condition are highly desired. The natriuretic and diuretic properties of the natriuretic peptides make them ideal candidates for the treatment of congestive heart failure. However, current therapeutics from this family of peptides are far from ideal and suffer from poor pharmacokinetic properties. In the last 20 years, there has been growing interest in NPs from reptilian venom due to high potency and stability. In the present work, Tadendocor (TDT), a chimeric NP, has been produced, which is a combination of the N- and C-terminal tails of taipan natriuretic peptide c (TNPc) from Oxyuranus microlepidotus with the 17-residue intramolecular ring of Dendroaspis natriuretic peptide (DNP) from Dendroaspis angusticeps. This peptide was found to possess increased stability to a range of endopeptidases and proteases and was active at human natriuretic peptide receptor A (hNPR-A) with similar potency to human atrial natriuretic peptide (hANP). Point mutations within the intramolecular ring further increased the potency at hNPR-A, with the H12R, N22G mutant being the most active. Mini-PEGylation with a variety of branched and linear PEG groups did not significantly affect the potency of Nle 29 TDT [H12R/N22G] at hNPR-A, but allowed for oral delivery in vivo. The attachment of a >20-kDa PEG group reduced the potency at hNPR-A by 10-fold but significantly increased the half-life in vivo. This chimeric snake NP represents a promising candidate for the development of a stable, potent NP therapeutic for heart failure.