1,6-cyclophellitol cyclosulfates: a new class of irreversible glycosidase inhibitor

DOI: 10.1021/acscentsci.7b00214

Authors: Marta Artola (Leiden University) , Liang Wu (University of York) , Maria J. Ferraz (Leiden University) , Chi-Lin Kuo (Leiden University) , Lluís Raich (Universitat de Barcelona) , Imogen Z. Breen (University of York) , Wendy A. Offen (University of York) , Jeroen D. C. Codée (Leiden University) , Gijsbert A. Van Der Marel (Leiden University) , Carme Rovira (Universitat de Barcelona; Fundació Catalana de Recerca i Estudis Avançats (ICREA)) , Johannes M. F. G. Aerts (Leiden University) , Gideon J. Davies (University of York) , Herman S. Overkleeft (Leiden University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Central Science

State: Published (Approved)
Published: July 2017
Diamond Proposal Number(s): 13587

Abstract: The essential biological roles played by glycosidases, coupled to the diverse therapeutic benefits of pharmacologically targeting these enzymes, provide considerable motivation for the development of new inhibitor classes. Cyclophellitol epoxides and aziridines are recently established covalent glycosidase inactivators. Inspired by the application of cyclic sulfates as electrophilic equivalents of epoxides in organic synthesis, we sought to test whether cyclophellitol cyclosulfates would similarly act as irreversible glycosidase inhibitors. Here we present the synthesis, conformational analysis, and application of novel 1,6-cyclophellitol cyclosulfates. We show that 1,6-epi-cyclophellitol cyclosulfate (α-cyclosulfate) is a rapidly reacting α-glucosidase inhibitor whose 4C1 chair conformation matches that adopted by α-glucosidase Michaelis complexes. The 1,6-cyclophellitol cyclosulfate (β-cyclosulfate) reacts more slowly, likely reflecting its conformational restrictions. Selective glycosidase inhibitors are invaluable as mechanistic probes and therapeutic agents, and we propose cyclophellitol cyclosulfates as a valuable new class of carbohydrate mimetics for application in these directions.

Journal Keywords: Aziridines; Peptides and proteins; Inhibitors; Inhibition; Conformation

Diamond Keywords: Enzymes

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 17/07/2017 08:50

Documents:
acscentscib.pdf

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)