Parallel synthesis and biological evaluation of different sizes of bicyclo[2,3]-Leu-enkephalin analogues

Xuyuan Gu, Jinfa Ying, Byoung Min, James P. Cain, Peg Davis, Patrick Willey, Edita Navratilova, Henry I. Yamamura, Frank Porreca, Victor J. Hruby

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Parallel synthesis of peptides and peptidomimetics has been an important approach to search for biologically active ligands. A novel systematic synthesis of different size bicyclic dipeptide mimetics was developed on solid-phase supports. By taking advantage of the enantioselective synthesis of ω-unsaturated amino acids and their N-methylated derivatives, the hemiaminal problem was prevented in the pathway to thiazolidine formation. The bicyclic dipeptide was generated on the solid-phase support in three steps by an unconventional method. By inserting this bicyclic scaffold into the synthesis of a larger bioactive peptide, 11 different sizes of bicyclo[2,3]- Leu-enkephalin analogues were synthesized in a fast and efficient way. Modeling studies show that a reversed turn structure at positions 2-3 was favored when an L- and L-bicyclic scaffold was used, and that an extended conformation at the N-terminal was favored when a D- and L-bicyclic scaffold was inserted. Binding affinities and bioassay studies show ligands with micromolar binding affinities and antagonist bioactivities for the [6,5]- and [7,5]-bicyclo-Leu-enkephalin analogues.

Original languageEnglish (US)
Pages (from-to)151-163
Number of pages13
JournalBiopolymers - Peptide Science Section
Volume80
Issue number2-3
DOIs
StatePublished - Jun 20 2005

Keywords

  • Bicyclic dipeptide
  • Leu-enkephalin
  • Solid-phase parallel synthesis
  • Synthetic methodology
  • β-turn mimetics

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Biomaterials
  • Organic Chemistry

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