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Design, synthesis and structural analysis of glucocerebrosidase imaging agents

DOI: 10.1002/chem.202102359 DOI Help

Authors: Gideon J. Davies (University of York) , Rhianna J. Rowland (University of York) , Yurong Chen (Leiden University) , Imogen Breen (University of York) , Liang Wu (University of York) , Wendy A. Offen (University of York) , Thomas Beenakker (Leiden University) , Qin Su (Leiden University) , Adrianus M. C. H. Van Den Nieuwendijk (Leiden University) , Johannes M. F. G. Aerts (Leiden University) , Marta Artola (Leiden University) , Herman S. Overkleeft (Leiden University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemistry – A European Journal

State: Published (Approved)
Published: September 2021
Diamond Proposal Number(s): 13587 , 18598

Abstract: Gaucher disease (GD) is a lysosomal storage disorder caused by inherited deficiencies in β-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, we synthesised a bi-functional aziridine ABP which we hoped would offer a 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.

Journal Keywords: Activity-based probes; Carbohydrates; Cyclitols; Fluorescent Probes; β-Glucocerebrosidase; Inhibitors; Structural Biology

Diamond Keywords: Gaucher Disease; Enzymes

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 29/09/2021 09:21

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Non-Communicable Diseases Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)