Activation of the Wnt Pathway by Small Peptides: Rational Design, Synthesis and Biological Evaluation

ChemMedChem. 2017 Dec 19;12(24):2074-2085. doi: 10.1002/cmdc.201700551. Epub 2017 Nov 29.

Abstract

A computational analysis of the X-ray structure of the low-density lipoprotein receptor-related protein 6 (LRP6) with the Dickkopf-1 (DKK1) C-terminal fragment has allowed us to rationally design a small set of decapeptides. These compounds behave as agonists of the canonical Wnt pathway in the micromolar range when tested on a dual luciferase Wnt functional assay in glioblastoma cells. Two of the oligopeptides showed a lack of cytotoxicity in human primary osteoblasts isolated from sponge bone tissue (femoral heads or knees of elderly patients). According to the mechanism of action, the studies revealed a dose- and time-dependent increase in the viability of human osteoblasts. These results may indicate a potential therapeutic application of this class of compounds in the treatment of bone diseases related to aging, such as osteoporosis.

Keywords: DKK1 mimetics; Wnt modulators; bone diseases; molecular dynamics; osteoporosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Cell Survival / drug effects
  • Cells, Cultured
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Female
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Models, Molecular
  • Molecular Conformation
  • Oligopeptides / chemical synthesis
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Osteoblasts / drug effects*
  • Osteoblasts / pathology
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • Time Factors
  • Wnt Signaling Pathway / drug effects*

Substances

  • DKK1 protein, human
  • Intercellular Signaling Peptides and Proteins
  • Oligopeptides
  • Small Molecule Libraries