Divergent synthesis of multifunctional molecular probes to elucidate the enzyme specificity of dipeptidic gamma-secretase inhibitors

ACS Chem Biol. 2007 Jun 15;2(6):408-18. doi: 10.1021/cb700073y. Epub 2007 May 25.


Divergent synthesis of multifunctional molecular probes based on caprolactam-derived dipeptidic gamma-secretase inhibitors (GSIs), Compound E (CE) and LY411575 analogue (DBZ), was efficiently accomplished by means of Cu(I)-catalyzed azide/alkyne fusion reaction. Photoaffinity labeling experiments using these derivatives coupled to photoactivatable and biotin moieties provided direct evidence that the molecular targets of CE and DBZ are the N-terminal fragment of presenilin 1 within the gamma-secretase complex. Moreover, these photoprobes directly targeted signal peptide peptidase. These data suggest that the divergent synthesis of molecular probes has been successfully applied to characterize the interaction of GSIs with their molecular targets and define the structural requirements for inhibitor binding to intramembrane-cleaving proteases.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / biosynthesis
  • Animals
  • HeLa Cells
  • Humans
  • Molecular Probes / chemical synthesis*
  • Presenilin-1 / metabolism
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology
  • Substrate Specificity / drug effects
  • Substrate Specificity / physiology


  • Molecular Probes
  • Presenilin-1
  • Protease Inhibitors
  • Amyloid Precursor Protein Secretases