Application of a Sulfoxonium Ylide Electrophile to Generate Cathepsin X-Selective Activity-Based Probes

Simon J. Mountford, Bethany M. Anderson, Bangyan Xu, Elean S.V. Tay, Monika Szabo, My Linh Hoang, Jiayin Diao, Luigi Aurelio, Rhiannon I. Campden, Erik Lindström, Erica K. Sloan, Robin M. Yates, Nigel W. Bunnett, Philip E. Thompson, Laura E. Edgington-Mitchell

Research output: Contribution to journalArticle

Abstract

Cathepsin X/Z/P is cysteine cathepsin with unique carboxypeptidase activity. Its expression is associated with cancer and neurodegenerative diseases, although its roles during normal physiology are still poorly understood. Advances in our understanding of its function have been hindered by a lack of available tools that can specifically measure the proteolytic activity of cathepsin X. We present a series of activity-based probes that incorporate a sulfoxonium ylide warhead, which exhibit improved specificity for cathepsin X compared to previously reported probes. We apply these probes to detect cathepsin X activity in cell and tissue lysates, in live cells and in vivo, and to localize active cathepsin X in mouse tissues by microscopy. Finally, we utilize an improved method to generate chloromethylketones, necessary intermediates for synthesis of acyloxymethylketones probes, by way of sulfoxonium ylide intermediates. In conclusion, the probes presented in this study will be valuable for investigating cathepsin X pathophysiology.

Original languageEnglish (US)
Pages (from-to)718-727
Number of pages10
JournalACS Chemical Biology
Volume15
Issue number3
DOIs
StatePublished - Mar 20 2020

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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  • Cite this

    Mountford, S. J., Anderson, B. M., Xu, B., Tay, E. S. V., Szabo, M., Hoang, M. L., Diao, J., Aurelio, L., Campden, R. I., Lindström, E., Sloan, E. K., Yates, R. M., Bunnett, N. W., Thompson, P. E., & Edgington-Mitchell, L. E. (2020). Application of a Sulfoxonium Ylide Electrophile to Generate Cathepsin X-Selective Activity-Based Probes. ACS Chemical Biology, 15(3), 718-727. https://doi.org/10.1021/acschembio.9b00961