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Dynamic Combinatorial Chemistry Affords Sugar-Based Molecules Targeting Bacterial Glucosyltranseferase as Potential Dental Biofilm Inhibitors

Hartman, A. M., Jumde, V. R., Elgaher, W. A. M., Te Poele, E. M., Dijkhuizen, L. & Hirsch, A. K. H., 16-Jun-2020, In : ChemMedChem. 11 p., cmdc.202000222.

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We applied dynamic combinatorial chemistry (DCC) to find novel ligands of the bacterial virulence factor glucosyltransferase (GTF) 180. GTFs are the major producers of extracellular polysaccharides, which are important factors in the initiation and development of cariogenic dental biofilms. Following a structure-based strategy, we designed a series of 36 glucose- and maltose-based acylhydrazones as substrate mimics. Synthesis of the required mono- and disaccharide-based aldehydes set the stage for DCC experiments. Analysis of the dynamic combinatorial libraries (DCLs) via UPLC-MS revealed major amplification of four compounds in the presence of GTF180. Moreover, we found that derivatives of the glucose-acceptor maltose at the C1-hydroxyl group are acting as glucose-donors and are cleaved by GTF180. The synthesized hits display medium to low binding affinity (KD values of 0.4-10.0 mm) according to surface plasmon resonance (SPR). In addition, they were investigated for the inhibitory activity using the GTF-activity assays. The early stage DCC study reveals that careful design of DCLs opens up easy access to a broad class of novel compounds that can be developed further as potential inhibitors.

Original languageEnglish
Article numbercmdc.202000222
Number of pages11
JournalChemMedChem
Publication statusE-pub ahead of print - 16-Jun-2020

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