Reversible pegylation prolongs the hypotensive effect of atrial natriuretic peptide

Maoz Nesher, Yelena Vachutinsky, Gil Fridkin, Yehuda Schwarz, Keren Sasson, Mati Fridkin, Yoram Shechter, David Lichtstein

Research output: Contribution to journalArticlepeer-review

Abstract

Natriuretic peptides (NP), including atrial natriuretic peptide (ANP), induce potent natriuresis and vasodilation and thereby generate hypotension in vivo. Despite intensive efforts, clinical application of NP as an antihypertensive agent is limited because of their short biological half-life and poor bioavailability. Recently, we have developed a strategy that facilitates slow release of peptides from PEG-peptide inactive conjugates, based on reversible pegylation. Peptides prepared by this approach undergo slow, spontaneous chemical hydrolysis at physiological conditions, releasing the native active peptide/protein drug from the inactive conjugates over prolonged periods. A PEG chain of 30 kDa was linked covalently to the α-amino side chain of the hormone via a MAL-Fmoc-NHS spacer, yielding PEG30-Fmoc- ANP, a prodrug that releases the native hormone upon incubation at physiological conditions. Bolus administration of native ANP to Wistar rats receiving adrenaline yields a short, transitory effect in lowering blood pressure (BP), reaching a maximum at 2 min, and then returning to control values after 12 to 25 min. In contrast, administration of PEG30-Fmoc-ANP lowered BP following a lag period of 50 min, and maintained low BP for a period exceeding 60 min. Saline or PEG30-Fmoc-Alanine were not effective in lowering BP in Wistar rats. These results show that the novel compound, PEG 30-Fmoc-ANP, is a reversible pegylated prodrug derivative that facilitates a prolonged BP lowering effect in rats and may be considered as a candidate for development into an antihypertensive drug.

Original languageEnglish
Pages (from-to)342-348
Number of pages7
JournalBioconjugate Chemistry
Volume19
Issue number1
DOIs
StatePublished - Jan 2008
Externally publishedYes

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