Login / Signup

Structure-Activity Relationship and Bioactivity of Short Analogues of ELABELA as Agonists of the Apelin Receptor.

Kien TrânAlexandre MurzaXavier SainsilyEugénie DelilePierre CouvineauJérôme CôtéDavid CoquerelMaude PeloquinMannix Auger-MessierMichel BouvierOlivier LesurPhilippe SarretEric Marsault
Published in: Journal of medicinal chemistry (2020)
ELABELA (ELA) is the second endogenous ligand of the apelin receptor (APJ). Although apelin-13 and ELA both target APJ, there is limited information on structure-activity relationship (SAR) of ELA. In the present work, we identified the shortest bioactive C-terminal fragment ELA23-32, which possesses high affinity for APJ (Ki 4.6 nM) and produces cardiorenal effects in vivo similar to those of ELA. SAR studies on conserved residues (Leu25, His26, Val29, Pro30, Phe31, Pro32) show that ELA and apelin-13 may interact differently with APJ. His26 and Val29 emerge as important for ELA binding. Docking and binding experiments suggest that Phe31 of ELA may bind to a tight groove distinct from that of Phe13 of Ape13, while the Phe13 pocket may be occupied by Pro32 of ELA. Further characterization of signaling profiles on the Gαi1, Gα12, and β-arrestin2 pathways reveals the importance of aromatic residue at the Phe31 or Pro32 position for receptor activation.
Keyphrases
  • structure activity relationship
  • anti inflammatory
  • transcription factor
  • healthcare
  • molecular dynamics simulations
  • small molecule
  • lymph node
  • amino acid