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Publication Abstract from PubMed

There is a vast genomic resource for enzymes active on carbohydrates. Lagging far behind, however, are functional chemical tools for the rapid characterization of carbohydrate-active enzymes. Activity-based probes (ABPs) offer one chemical solution to these issues with ABPs based upon cyclophellitol epoxide and aziridine covalent and irreversible inhibitors representing a potent and widespread approach. Such inhibitors for enzymes active on polysaccharides are potentially limited by the requirement for several glycosidic bonds, themselves substrates for the enzyme targets. Here we show that non-hydrolysable trisaccharide can be synthesized and applied even to enzymes with challenging subsite requirements. We find that incorporation of carbasugar moieties, which we accomplished by cuprate-assisted regioselective trans-diaxial epoxide opening of carba-mannal we synthesised for this purpose, yields inactivators that act as powerful activity-based inhibitors for a-1,6 endo-mannanases. 3-D structures at 1.35 - 1.47 A resolutions confirm the design rationale and binding to the enzymatic nucleophile. Carbasugar oligosaccharide cyclophellitols offer a powerful new approach for the design of robust endoglycosidase inhibitors, while the synthesis procedures presented here should allow adaptation towards activity-based endoglycosidase probes as well as configurational isosteres targeting other endoglycosidase families.

The Development of Non-Hydrolysable Oligosaccharide Activity-Based Inactivators for Endoglycanases: A Case Study on a-1,6 Mannanases.,Overkleeft HS, Schroder S, Offen W, Males A, Jin Y, de Boer C, Enotarpi J, van der Marel G, Florea B, Codee J, Davies G Chemistry. 2021 Apr 20. doi: 10.1002/chem.202101255. PMID:33878235^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.