New Irreversible α-l-Iduronidase Inhibitors and Activity-Based Probes

Marta Artola*, Chi Lin Kuo, Stephen A. McMahon, Verena Oehler, Thomas Hansen, Martijn van der Lienden, Xu He, Hans van den Elst, Bogdan I. Florea, Allison R. Kermode, Gijsbert A. van der Marel, Tracey M. Gloster, Jeroen D.C. Codée, Herman S. Overkleeft, Johannes M.F.G. Aerts

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Cyclophellitol aziridines are potent irreversible inhibitors of retaining glycosidases and versatile intermediates in the synthesis of activity-based glycosidase probes (ABPs). Direct 3-amino-2-(trifluoromethyl)quinazolin-4(3H)-one-mediated aziridination of l-ido-configured cyclohexene has enabled the synthesis of new covalent inhibitors and ABPs of α-l-iduronidase, deficiency of which underlies the lysosomal storage disorder mucopolysaccharidosis type I (MPS I). The iduronidase ABPs react covalently and irreversibly in an activity-based manner with human recombinant α-l-iduronidase (rIDUA, Aldurazyme®). The structures of IDUA when complexed with the inhibitors in a non-covalent transition state mimicking form and a covalent enzyme-bound form provide insights into its conformational itinerary. Inhibitors 1–3 adopt a half-chair conformation in solution (4H3 and 3H4), as predicted by DFT calculations, which is different from the conformation of the Michaelis complex observed by crystallographic studies. Consequently, 1–3 may need to overcome an energy barrier in order to switch from the 4H3 conformation to the transition state (2, 5B) binding conformation before reacting and adopting a covalent 5S1 conformation. rIDUA can be labeled with fluorescent Cy5 ABP 2, which allows monitoring of the delivery of therapeutic recombinant enzyme to lysosomes, as is intended in enzyme replacement therapy for the treatment of MPS I patients.

Original languageEnglish
Pages (from-to)19081-19088
Number of pages8
JournalChemistry - A European Journal
Volume24
Issue number71
DOIs
Publication statusPublished - 17 Dec 2018

Keywords

  • activity-based protein profiling
  • conformational analysis
  • cyclophellitol aziridines
  • glycosidase
  • irreversible inhibitors

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