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Keywords:

  • GPR54;
  • kisspeptin;
  • structure-activity relationship;
  • CF[BOND]HN hydrogen bonding

Abstract

GPR54 is a Gq-protein coupled receptor involved in cancer metastasis and regulation of the endocrine system. GPR54 activation by endogenous ligands attenuates the mobility of carcinomas and stimulates the secretion of gonadotropin-releasing hormone. GPR54 agonists are, therefore, potential therapeutic candidates for cancer metastasis and hormonal diseases. Pentapeptide derivatives of kisspeptin C-terminus were identified as potent GPR54 agonists in our previous studies. In the present study, we investigated the structure-activity relationship of a variety of pentapeptides having various fluorine-substituted benzoyl groups at the N-terminus. Among these, a 4-fluorobenzoyl derivative was the most potent agonist. On the other hand, the derivatives having multiple fluoro-substituting groups showed less binding affinity. NMR analysis of these peptides and their N-terminal partial structures suggested that fluorine substituents affect the benzoyl conformation. o-Monofluorobenzoyl is likely to be in a coplanar conformation due to the intramolecular CF[BOND]HN hydrogen bonding between o-fluorine and amide hydrogen; the o,o-difluorobenzoyl moiety exists in a distorted conformation probably due to the steric hindrance and/or electrostatic repulsion between two o-fluorine atoms and carbonyl oxygen. © 2008 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 90: 503–511, 2008.

This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com