Synthetic Modification within the “RPRL” Region of Apelin Peptides: Impact on Cardiovascular Activity and Stability to Neprilysin and Plasma Degradation

Apelin
is an important mammalian peptide hormone with a range of physiological
roles, especially in the cardiovascular system. The apelinergic system
is a promising target for treatment of disease, but this remains to
be realized due to rapid proteolysis of apelin-derived peptides by
proteases, including neprilysin (NEP). The synthetic analogues modified
within the NEP degradation site (“RPRL” motif) showed
improved in vitro proteolytic stability while maintaining receptor-binding affinities,
with three candidate peptides retaining full cardiovascular activities
for potential therapeutic application. Many such analogues proved
physiologically inactive even with relatively conservative modifications,
highlighting the importance of this region for full agonist activity
of this peptide hormone.