Potential Dental Biofilm Inhibitors: Dynamic Combinatorial Chemistry Affords Sugar-Based Molecules that Target Bacterial Glucosyltransferase.
Potential Dental Biofilm Inhibitors: Dynamic Combinatorial Chemistry Affords Sugar-Based Molecules that Target Bacterial Glucosyltransferase.
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DOI：
10.1002/cmdc.202000222
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发表时间：
2021-01-08
期刊：
影响因子：
3.4
通讯作者：
Hirsch AKH
中科院分区：
文献类型：
--
作者：
Hartman AM;Jumde VR;Elgaher WAM;Te Poele EM;Dijkhuizen L;Hirsch AKH
我们应用动态组合化学（DCC）来寻找细菌毒力因子葡糖基转移酶（GTF）180的新配体。GTFs是牙源性生物膜形成的重要因素，是牙源性生物膜形成的重要因素。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腙作为底物模拟物。所需的单糖和二糖基醛的合成为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GTF 180存在下四种化合物的主要扩增。此外，我们发现葡萄糖受体麦芽糖在C1-羟基上的衍生物作为葡萄糖供体，并被GTF 180裂解。根据表面等离子体共振，合成的命中显示中等至低结合亲和力（KD值为0.4-10.0 mm）。此外，在GTF活性试验中研究了它们的抑制活性。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。 延迟衰减：基于结构的设计结合基于酰腙的动态组合化学（DCC）提供了葡聚糖蔗糖酶（GS）的抑制剂，GS是导致龋齿的主要毒力因子。DCC提供了一种简单的途径，用于以基于葡萄糖和麦芽糖的酰腙的形式发现GS的第一次命中，模拟GS底物。
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. Delay decay: Structure‐based design in combination with acylhydrazone‐based dynamic combinatorial chemistry (DCC) afforded inhibitors of glucansucrase (GS), the main virulence factor responsible for dental caries. DCC offered a facile pathway for finding the first hits of GS in the form of glucose‐ and maltose‐based acylhydrazones, mimicking the GS substrate.
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影响因子：
4.2
作者：
Hartman, Alwin M.;Elgaher, Walid A. M.;Hirsch, Anna K. H.
通讯作者：
Hirsch, Anna K. H.
影响因子：
1
作者：
Lin, Chang-Ching;Huang, Li-Cheng;Lin, Chun-Cheng
通讯作者：
Lin, Chun-Cheng
影响因子：
21.8
作者：
Bhat, Venugopal T.;Caniard, Anne M.;Luksch, Torsten;Brenk, Ruth;Campopiano, Dominic J.;Greaney, Michael F.
通讯作者：
Greaney, Michael F.
影响因子：
7.3
作者：
Irwin JJ;Duan D;Torosyan H;Doak AK;Ziebart KT;Sterling T;Tumanian G;Shoichet BK
通讯作者：
Shoichet BK
影响因子：
3.9
作者：
Elgaher, Walid A. M.;Fruth, Martina;Hartmann, Rolf W.
通讯作者：
Hartmann, Rolf W.