Carba-cyclophellitols Are Neutral Retaining-Glucosidase Inhibitors

Thomas J.M. Beenakker, Dennis P.A. Wander, Wendy A. Offen, Marta Artola, Lluís Raich, Maria J. Ferraz, Kah Yee Li, Judith H.P.M. Houben, Erwin R. Van Rijssel, Thomas Hansen, Gijsbert A. Van Der Marel, Jeroen D.C. Codée, Johannes M.F.G. Aerts, Carme Rovira, Gideon J. Davies*, Herman S. Overkleeft

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review


The conformational analysis of glycosidases affords a route to their specific inhibition through transition-state mimicry. Inspired by the rapid reaction rates of cyclophellitol and cyclophellitol aziridine - both covalent retaining β-glucosidase inhibitors - we postulated that the corresponding carba "cyclopropyl" analogue would be a potent retaining β-glucosidase inhibitor for those enzymes reacting through the 4H3 transition-state conformation. Ab initio metadynamics simulations of the conformational free energy landscape for the cyclopropyl inhibitors show a strong bias for the 4H3 conformation, and carba-cyclophellitol, with an N-(4-azidobutyl)carboxamide moiety, proved to be a potent inhibitor (Ki = 8.2 nM) of the Thermotoga maritima TmGH1 β-glucosidase. 3-D structural analysis and comparison with unreacted epoxides show that this compound indeed binds in the 4H3 conformation, suggesting that conformational strain induced through a cyclopropyl unit may add to the armory of tight-binding inhibitor designs.

Original languageEnglish
Pages (from-to)6534-6537
Number of pages4
JournalJournal of the American Chemical Society
Issue number19
Publication statusPublished - 17 May 2017


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