Journal of Medicinal Chemistry
Journal of Medicinal Chemistry
5 years ago

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

Synthetic Modification within the “RPRL” Region of Apelin Peptides: Impact on Cardiovascular Activity and Stability to Neprilysin and Plasma Degradation
John C. Vederas, Tyler McDonald, Conrad Fischer, Shaun M. K. McKinnie, Catherine Llorens-Cortes, Wang Wang, Gavin Y. Oudit, Xavier Iturrioz, Kevin R. Kalin
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.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00723

DOI: 10.1021/acs.jmedchem.7b00723

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