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Mucopolysaccharidosis type I

New irreversible α-L-iduronidase inhibitors and activity-based probes.
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New irreversible α-L-iduronidase inhibitors and activity-based probes.

Chemistry. 2018 Oct 11;:

Authors: Artola M, Kuo CL, McMahon SA, Oehler V, Hansen T, van der Lienden M, He X, van den Elst H, Florea BI, Kermode AR, Gloster TM, van der Marel GA, Codée JDC, Overkleeft HS, Aerts JMFG

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 on 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 structure of IDUA in complex with the inhibitors in a non-covalent transition state mimicking form and covalent enzyme-bound form provides insights into the conformational itinerary employed by IDUA. Inhibitors 1-3 adopt a half-chair conformation in solution (4H3 and 3H4), as observed by DFT calculations, which is different from the Michaelis complex conformation observed by crystallographic studies, and consequently 1-3 may need to overcome an energetic barrier in order to switch from the 4H3 to the transition state (2,5B) binding conformation before reacting and adopting a covalent 5S1 conformation. The fluorescent Cy5 ABP 2 labels rIDUA and allows monitoring the delivery of therapeutic recombinant enzyme to lysosomes, as is intended in enzyme replacement therapy for the treatment of MPS I patients.

PMID: 30307091 [PubMed - as supplied by publisher]

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