Potential Dental Biofilm Inhibitors: Dynamic Combinatorial Chemistry Affords Sugar-Based Molecules that Target Bacterial Glucosyltransferase.,ChemMedChem

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Potential Dental Biofilm Inhibitors: Dynamic Combinatorial Chemistry Affords Sugar-Based Molecules that Target Bacterial Glucosyltransferase.
ChemMedChem ( IF 3.6 ) Pub Date : 2020-06-16 , DOI: 10.1002/cmdc.202000222
Alwin M Hartman _{1,

2,

3} , Varsha R Jumde _{1,

3} , Walid A M Elgaher ₁ , Evelien M Te Poele _{4,

5} , Lubbert Dijkhuizen _{4,

5} , Anna K H Hirsch _{1,

2,

3}

Affiliation

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) by 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‐hydroxy group act as glucose‐donors and are cleaved by GTF180. The synthesized hits display medium to low binding affinity (K_D values of 0.4–10.0 mm) according to surface plasmon resonance. In addition, they were investigated for inhibitory activity in 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.

中文翻译：

潜在的牙科生物膜抑制剂：动态组合化学提供靶向细菌葡萄糖基转移酶的糖基分子。

我们应用动态组合化学 (DCC) 来寻找细菌毒力因子葡萄糖基转移酶 (GTF) 180 的新配体。 GTF 是细胞外多糖的主要生产者，是致龋牙齿生物膜的启动和发展的重要因素。遵循基于结构的策略，我们设计了一系列 36 种基于葡萄糖和麦芽糖的酰基腙作为底物模拟物。所需的单糖和双糖醛的合成为 DCC 实验奠定了基础。通过 UPLC-MS 对动态组合文库 (DCL) 的分析揭示了在 GTF180 存在下四种化合物的主要扩增。此外，我们发现 C1-羟基上的葡萄糖受体麦芽糖衍生物充当葡萄糖供体并被 GTF180 裂解。根据表面等离子体共振，K _D值为 0.4–10.0 m m )。此外，还研究了它们在 GTF 活性测定中的抑制活性。早期 DCC 研究表明，仔细设计 DCL 可以轻松获得广泛的新型化合物，这些化合物可以进一步开发为潜在的抑制剂。

更新日期：2020-06-16

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