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

Haruhiko Fuwa, Yasuko Takahashi, Yu Konno, Naoto Watanabe, Hiroyuki Miyashita, Makoto Sasaki, Hideaki Natsugaril, Toshiyuki Kan, Tohru Fukuyama, Taisuke Tomita, Takeshi Iwatsubo

Research output: Contribution to journalArticlepeer-review

85 Citations (Scopus)

Abstract

Divergent synthesis of multifunctional molecular probes based on caprolactam-derived dipeptidic γ-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 γ-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.

Original languageEnglish
Pages (from-to)408-418
Number of pages11
JournalACS Chemical Biology
Volume2
Issue number6
DOIs
Publication statusPublished - 2007 Jun 1

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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