Enhancing glycan stability via site-selective fluorination: modulating substrate orientation by molecular design

Axer, A., Jumde, R. P., Adam, S., Faust, A., Schäfers, M., Fobker, M., Koehnke, J. , Hirsch, A. K. H. and Gilmour, R. (2021) Enhancing glycan stability via site-selective fluorination: modulating substrate orientation by molecular design. Chemical Science, 12, pp. 1286-1294. (doi: 10.1039/D0SC04297H)

Abstract

Single site OH → F substitution at the termini of maltotetraose leads to significantly improved hydrolytic stability towards α-amylase and α-glucosidase relative to the natural compound. To explore the effect of molecular editing, selectively modified oligosaccharides were prepared via a convergent α-selective strategy. Incubation experiments in purified α-amylase and α-glucosidase, and in human and murine blood serum, provide insight into the influence of fluorine on the hydrolytic stability of these clinically important scaffolds. Enhancements of ca. 1 order of magnitude result from these subtle single point mutations. Modification at the monosaccharide furthest from the probable enzymatic cleavage termini leads to the greatest improvement in stability. In the case of α-amylase, docking studies revealed that retentive C2-fluorination at the reducing end inverts the orientation in which the substrate is bound. A co-crystal structure of human α-amylase revealed maltose units bound at the active-site. In view of the evolving popularity of C(sp3)–F bioisosteres in medicinal chemistry, and the importance of maltodextrins in bacterial imaging, this discovery begins to reconcile the information-rich nature of carbohydrates with their intrinsic hydrolytic vulnerabilities.

• Item Type: Articles
• Additional Information: We acknowledge generous financial support from the WWU Munster, the European Research Council (ERC Starter Grant - ¨ Project number 336376-ChMiFluorS and ERC Consolidator Grant – Project Number 818949-RECON, to RG), the Interdisciplinary Centre for Clinical Research (IZKF), Munster, Ger- ¨ many (Fau2/014/17), the DFG Cluster of Excellence “Cells in Motion - CiM” (FF-2013-10) and a stipend of the CiM-IMPRS graduate programme, Munster, Germany (to A. A.) and the ¨ DFG Emmy-Noether programme (KO 4116/3-2 to J. K.). The European Commission is acknowledged for an Intra-European Marie Skłodowska-Curie actions fellowship under Horizon2020 (796089–NovInDXS, R. P. J.) and the ERC (Starter Grant 757913 to A. K. H. H.).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Koehnke, Professor Jesko
• Authors: Axer, A., Jumde, R. P., Adam, S., Faust, A., Schäfers, M., Fobker, M., Koehnke, J., Hirsch, A. K. H., and Gilmour, R.
• College/School: College of Science and Engineering > School of Chemistry
• Journal Name: Chemical Science
• Publisher: Royal Society of Chemistry
• ISSN: 2041-6520
• ISSN (Online): 2041-6539
• Published Online: 23 November 2020
• Copyright Holders: Copyright © 2021 The Author(s)
• First Published: First published in Chemical Science 12:1286-1294
• Publisher Policy: Reproduced under a Creative Commons licence