New templates for syntheses of ring-fused, C(10) beta-turn peptidomimetics leading to the first reported small-molecule mimic of neurotrophin-3

J Med Chem. 2002 Sep 26;45(20):4387-90. doi: 10.1021/jm0255421.

Abstract

beta-Turn peptidomimetics 1 were designed to mimic hot spots of neurotrophin-3 (NT-3) and others. Solid-phase syntheses of these were developed, though limitations were encountered with scale-up. Consequently, an alternative design with 2 was investigated. 1 and 2 favored distorted type I beta-turn conformations in solution. It was found that peptidomimetic 2b has NT-3-like neurotrophic activity in cell survival assays, selectively binds the NT-3 receptor TrkC, and induces the tyrosine phosphorylation of the TrkC receptor.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Animals
  • Cell Survival / drug effects
  • Circular Dichroism
  • Flow Cytometry
  • Mice
  • Molecular Mimicry
  • Neurotrophin 3 / chemistry*
  • Peptides / chemistry*
  • Peptides, Cyclic / chemical synthesis*
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology
  • Phosphorylation
  • Protein Structure, Secondary
  • Receptor, trkA / metabolism
  • Receptor, trkC / metabolism
  • Tyrosine / metabolism

Substances

  • Neurotrophin 3
  • Peptides
  • Peptides, Cyclic
  • cyclo(lysyl-serinamido-4-carbamoylphenylmethylamino-3-nitrobenzoyl)
  • Tyrosine
  • Receptor, trkA
  • Receptor, trkC