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New irreversible α- l -Iduronidase inhibitors and activity-based probes

DOI: 10.1002/chem.201804662 DOI Help

Authors: Marta Artola (Leiden University) , Chi-lin Kuo (Leiden University) , Stephen Mcmahon (University of St Andrews) , Verena Oehler (University of St Andrews) , Thomas Hansen (Leiden University) , Martijn Van Der Lienden (Leiden University) , Xu He (Simon Fraser University) , Hans Van Den Elst (Leiden University) , Bogdan I. Florea (Leiden University) , Allison R. Kermode (Simon Fraser University) , Gijsbert A. Van Der Marel (Leiden University) , Tracey M. Gloster (University of St Andrews) , Jeroen D. C. Codée (Leiden University) , Herman S. Overkleeft (Leiden University) , Johannes M. F. G. Aerts (Leiden University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemistry - A European Journal , VOL 42

State: Published (Approved)
Published: November 2018
Diamond Proposal Number(s): 14980

Open Access Open Access

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.

Journal Keywords: activity-based protein profiling; conformational analysis; cyclophellitol aziridines; glycosidase; irreversible inhibitors

Subject Areas: Chemistry, Biology and Bio-materials

Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography