New irreversible α-ʟ-iduronidase inhibitors and activity-based probes
MetadataShow full item record
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 ʟ‐ido‐configured cyclohexene has enabled the synthesis of new covalent inhibitors and ABPs of α‐ʟ‐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‐ʟ‐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.
Artola , M , Kuo , C-L , McMahon , S A , Oehler , V , Hansen , T , van der Lienden , M , He , X , van den Elst , H , Florea , B I , Kermode , A R , van der Marel , G A , Gloster , T M , Codée , J D C , Overkleeft , H S & Aerts , J M F G 2018 , ' New irreversible α-ʟ-iduronidase inhibitors and activity-based probes ' Chemistry - A European Journal , vol. Early View . https://doi.org/10.1002/chem.201804662
Chemistry - A European Journal
© 2018 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
DescriptionWe thank The Netherlands Organization for Scientific Research (NWO-CW, ChemThem grant to J.M.F.G.A. and H.S.O.), the European Research Council (ERC-2011-AdG290836 “Chembiosphing”, to H.S.O.) and Sanofi Genzyme (research grant to J.M.F.G.A. and H.S.O. and postdoctoral contract to M.A.). We acknowledge ChemAxon for kindly providing the Instant JChem software to manage our compound library. T.M.G., V.O. and S.A.M. are supported by a Wellcome Trust Research Career Development Fellowship and Institutional Strategic Support Funding.
Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.