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Elucidation of the Structure–Activity Relationships of Apelin: Influence of Unnatural Amino Acids on Binding, Signaling, and Plasma Stability
Author(s) -
Murza Alexandre,
Parent Alexandre,
BessererOffroy Elie,
Tremblay Hugo,
Karadereye Félix,
Beaudet Nicolas,
Leduc Richard,
Sarret Philippe,
Marsault Éric
Publication year - 2012
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100492
Subject(s) - apelin , receptor , chemistry , amino acid , g protein coupled receptor , peptide , endogeny , hormone , biochemistry , ligand (biochemistry) , stereochemistry , microbiology and biotechnology , biology
Apelin is the endogenous ligand of the APJ receptor, a member of the G‐protein‐coupled receptor family. The apelin–APJ complex has been detected in many tissues and is emerging as a promising target for several pathophysiological conditions. There is currently little information on the structure–activity relationship (SAR) of the apelin hormone. In an effort to better delineate SAR, we synthesized analogues of apelin‐13 modified at selected positions with unnatural amino acids, with a particular emphasis on the C‐terminal portion. Analogues were then tested in binding and functional assays by evaluating G i/o ‐mediated decreases in cAMP levels and by assessing β‐arrestin2 recruitment to the APJ receptor. The plasma stability of new compounds was also assessed. Several analogues were found to possess increased binding and higher stability than the parent peptide.