Design of Peptide Hydroxamate-Based Photoreactive Activity-Based Probes of Zinc-Dependent Metalloproteases

Paul P. Geurink, Theo Klein, Laurette Prely, Krisztina Paal, Michiel A. Leeuwenburgh, Gijs A. van der Marel, Henk F. Kauffman, Herman S. Overkleeft*, Rainer Bischoff*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

9 Citations (Scopus)

Abstract

Metalloproteases (ADAMs, MMPs) are multidomain proteins that play key roles in extracellular matrix remodelling and degradation, in cell-cell and cell-matrix interactions and in the proteolytic liberation of membrane-anchored proforms of cytokines and growth factors, the so-called ectodomain shedding. In this work we describe the development of photoactivatable activity-based probes with which active metalloproteases can be visualised. Our probes are based on the succinyl hydroxamate motif and differ in the positioning of the trifluoromethylphenyldiazirine photoreactive group. We demonstrate that directing the photoactivatable group towards the S1' pocket yields activity-based probes more effective than the corresponding probe with the photoactivatable group directed towards the S2' pocket.

Original languageEnglish
Pages (from-to)2100-2112
Number of pages13
JournalEuropean Journal of Organic Chemistry
Volume2010
Issue number11
DOIs
Publication statusPublished - Apr-2010

Keywords

  • Metalloenzymes
  • Activity-based profiling
  • Photoaffinity labeling
  • Diazirine
  • Alkylation
  • Diastereoselectivity
  • NECROSIS-FACTOR-ALPHA
  • MATRIX METALLOPROTEINASES
  • FUNCTIONAL PROTEOMICS
  • ELASTOLYTIC ACTIVITY
  • PHOTOAFFINITY PROBE
  • COMPLEX PROTEOMES
  • MMP INHIBITORS
  • CELL
  • PROTEASOME
  • AFFINITY

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