Evaluation of novel cyclic analogues of apelin

Int J Mol Med. 2008 Oct;22(4):547-52.


Apelin regulates various cell signaling processes through interaction with its specific cell-surface receptor, APJ, which is a member of a seven transmembrane G protein-coupled receptor superfamily. To develop a novel apelin analogue, we synthesized cyclic analogues of minimal apelin fragment RPRLSHKGPMPF (apelin-12), and evaluated their bioactivities in a recombinant human APJ-expressed cell line. Three cyclic analogues were synthesized: cyclo apelin-12 (C1) in combination with amino-terminal to carboxy-terminal, cyclourea apelin-12 (C3) in combination with amino-terminal and amino acid side chain at positions 7, and cyclic apelin-12 (C4) in combination with amino acid side chain at positions 7 to carboxy-terminal. All cyclic analogues exhibited dose-dependent inhibitory effects against forskolin-induced cyclic adenosine monophosphate (cAMP) accumulation, and the maximal effects were almost abolished by pertussis toxin (PTx) treatment. Moreover, they could modulate the intracellular signaling pathways composed of Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) serine/threonine protein kinases in PTx-sensitive manner. This is the first approach to apply cyclization on apelin, and these results provide the basis for the development of drug-like apelin analogues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Apelin Receptors
  • Cell Line
  • Cyclic AMP / metabolism
  • Dose-Response Relationship, Drug
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Intercellular Signaling Peptides and Proteins / chemistry
  • Intercellular Signaling Peptides and Proteins / pharmacology*
  • Molecular Sequence Data
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology*
  • Pertussis Toxin / pharmacology
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, G-Protein-Coupled / metabolism
  • Time Factors


  • APLNR protein, human
  • Apelin Receptors
  • Intercellular Signaling Peptides and Proteins
  • Peptides, Cyclic
  • Receptors, G-Protein-Coupled
  • apelin-12 peptide
  • Cyclic AMP
  • Pertussis Toxin
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases