Fmoc-based solid-phase synthesis of GPR54-agonistic pentapeptide derivatives containing alkene- and fluoroalkene-dipeptide isosteres

Biopolymers. 2007;88(2):272-8. doi: 10.1002/bip.20676.

Abstract

Fmoc-protected Phe-Gly-type (Z)-alkene dipeptide isostere (ADI) and (E)-fluoroalkene dipeptide isostere (FADI) were synthesized and applied to Fmoc-based solid-phase peptide synthesis (SPPS). These cis-peptide bond mimetics were introduced into a bioactive pentapeptide [H-Amb-Phe-Gly-Leu-Arg-Trp-NH(2); Amb = 4-(aminomethyl) benzoic acid], which has potent GPR54 agonistic activity. The resulting pentapeptide derivatives showed low GPR54 agonistic activity, as compared with the parent peptide and (E)-ADI-containing derivative. This suggests that the trans-amide conformer of Phe-Gly peptide bond of the parent peptide would be significantly important for bioactivity. Contrary to our expectations, a (Z)-FADI-containing derivative exhibited essentially no activity, revealing the necessity of critical validation of FADI-bioisosterism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkenes / chemistry
  • Amino Acids
  • Dipeptides / chemical synthesis
  • Dipeptides / chemistry
  • Dipeptides / pharmacology
  • Fluorenes
  • Humans
  • In Vitro Techniques
  • Molecular Structure
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, Kisspeptin-1

Substances

  • Alkenes
  • Amino Acids
  • Dipeptides
  • Fluorenes
  • KISS1R protein, human
  • N(alpha)-fluorenylmethyloxycarbonylamino acids
  • Oligopeptides
  • Receptors, G-Protein-Coupled
  • Receptors, Kisspeptin-1