From Covalent Glycosidase Inhibitors to Activity-Based Glycosidase Probes

• Published in: Chemistry : a European journal Vol. 20; no. 35; pp. 10864 - 10872
• Main Authors: Willems, Lianne I., Jiang, Jianbing, Li, Kah-Yee, Witte, Martin D., Kallemeijn, Wouter W., Beenakker, Thomas J. N., Schröder, Sybrin P., Aerts, Johannes M. F. G., van der Marel, Gijsbert A., Codée, Jeroen D. C., Overkleeft, Hermen S.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 25.08.2014; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Subjects: Chemistry; Covalence; Displacement; Drug Design; Enzyme Activation - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes; glycobiology; Glycosidases; Glycoside Hydrolases - antagonists & inhibitors; Glycoside Hydrolases - metabolism; Hydrolysis; Molecular Probes - chemistry; Molecular Structure; Profiling; Protease; protein profiling; Proteins; enzymes; glycosidases; protein profiling; proteins; glycobiology
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201404014

Activity‐based protein profiling has emerged as a powerful discovery tool in chemical biology and medicinal chemistry research. Success of activity‐based protein profiling hinges on the presence of compounds that can covalently and irreversibly bind to enzymes, do so selectively in the context of complex biological samples, and subsequently report on the selected pool of proteins. Such tagged molecules featuring an electrophilic trap, termed activity‐based probes, have been developed with most success for serine hydrolases and various protease families (serine proteases, cysteine proteases, proteasomes). This concept presents the current progress and future directions in the design of activity‐based probes targeting retaining glycosidases, enzymes that employ a double displacement mechanism in the hydrolysis of glycosidic bonds with overall retention. In contrast to inverting glycosidases, retaining glycosidases form a covalent intermediate with their substrates during the catalytic process and are therefore amenable to activity‐based protein profiling studies. Protein profiling: This Concept presents the current progress and future directions in the design of activity‐based probes targeting retaining glycosidases, enzymes that employ a double displacement mechanism in the hydrolysis of glycosidic bonds with overall retention (see figure).