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dc.contributor.authorAxer, Alexander
dc.contributor.authorJumde, Ravindra P.
dc.contributor.authorAdam, Sebastian
dc.contributor.authorFaust, Andreas
dc.contributor.authorSchäfers, Michael
dc.contributor.authorFobker, Manfred
dc.contributor.authorKoehnke, Jesko
dc.contributor.authorHirsch, Anna K.H.
dc.contributor.authorGilmour, Ryan
dc.date.accessioned2021-03-02T12:25:43Z
dc.date.available2021-03-02T12:25:43Z
dc.date.issued2021-01-28
dc.identifier.citationChem. Sci., 2021,12, 1286-1294.en_US
dc.identifier.issn20416520
dc.identifier.doi10.1039/d0sc04297h
dc.identifier.urihttp://hdl.handle.net/10033/622760
dc.description.abstractingle 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 preparedviaa 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 ofca. 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. © The Royal Society of Chemistry 2020.en_US
dc.description.sponsorshipWestern Washington Universityen_US
dc.language.isoenen_US
dc.publisherRoyal Chemistry Society (RCS)en_US
dc.relationinfo:eu-repo/grantAgreement/EC/H2020/ 757913en_US
dc.rightsopenAccessen_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.titleEnhancing glycan stabilityviasite-selective fluorination: modulating substrate orientation by molecular designen_US
dc.typeArticleen_US
dc.identifier.eissn20416539
dc.contributor.departmentHIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.en_US
dc.identifier.journalChemical Scienceen_US
dc.identifier.scopusidSCOPUS_ID:85100469229
dc.source.volume12
dc.source.issue4
dc.source.beginpage1286
dc.source.endpage1294
refterms.dateFOA2021-03-02T12:25:44Z
dc.source.journaltitleChemical Science


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