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Design, Synthesis and Structural Analysis of Glucocerebrosidase Imaging Agents

Lookup NU author(s): Rhianna RowlandORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Gaucher disease (GD) is a lysosomal storage disorder caused by inherited deficiencies in beta-glucocerebrosidase (GBA). Current treatments require rapid disease diagnosis and a means of monitoring therapeutic efficacy, both of which may be supported by the use of GBA-targeting activity-based probes (ABPs). Here, we report the synthesis and structural analysis of a range of cyclophellitol epoxide and aziridine inhibitors and ABPs for GBA. We demonstrate their covalent mechanism-based mode of action and uncover binding of the new N-functionalised aziridines to the ligand binding cleft. These inhibitors became scaffolds for the development of ABPs; the O6-fluorescent tags of which bind in an allosteric site at the dimer interface. Considering GBA's preference for O6- and N-functionalised reagents, a bi-functional aziridine ABP was synthesized as a potentially more powerful imaging agent. Whilst this ABP binds to two unique active site clefts of GBA, no further benefit in potency was achieved over our first generation ABPs. Nevertheless, such ABPs should serve useful in the study of GBA in relation to GD and inform the design of future probes.

Publication metadata

Author(s): Rowland RJ, Chen J, Breen I, Wu L, Offen WA, Beenakker TJM, Su Q, van den Nieuwendijk AMCH, Aerts JMFG, Perez de Azanza ME, Overkleeft HS, Davies GJ

Publication type: Article

Publication status: Published

Journal: Chemistry - A European Journal

Year: 2021

Volume: 27

Issue: 66

Pages: 16377-16388

Print publication date: 25/11/2021

Online publication date: 27/09/2021

Acceptance date: 02/04/2018

Date deposited: 22/12/2021

ISSN (print): 0947-6539

ISSN (electronic): 1521-3765

Publisher: Wiley


DOI: 10.1002/chem.202102359


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