Hexosamine template. A platform for modulating gene expression and for sugar-based drug discovery.
Hexosamine template. A platform for modulating gene expression and for sugar-based drug discovery.
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DOI：
10.1021/jm801661m
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发表时间：
2009-04-23
影响因子：
7.3
通讯作者：
Yarema KJ
中科院分区：
文献类型：
--
作者：
Elmouelhi N;Aich U;Paruchuri VD;Meledeo MA;Campbell CT;Wang JJ;Srinivas R;Khanna HS;Yarema KJ
这项研究调查了短链脂肪酸(SCFA)-氨基己糖杂化分子产生的细胞反应的广度，这是一类长期用于“代谢性糖工程”的化合物，现在正成为候选药物。首先，“混合匹配”策略表明，添加到同一核心糖中的不同SCFA(正丁酸盐和醋酸酯)改变了生物活性，补充了先前的结果[Campbell等人，(2008)J.Med。化学。51,8135-8147]其中单一类型的SCFA引起不同的反应。然后，微阵列分析比较了区域异构化修饰的ManNAc、GlcNAc和GalNAc类似物在MDA-MB-231细胞中产生的转录反应。这些数据通过对ID1、TP53、HPSE、NQO1、Egr1和VEGFA的qRT-PCR或Western分析得到验证，显示出双管齐下的反应，其中一组核心基因由所有类似物协调调节，而每个类似物同时唯一地调节更多的基因。最后，自动对接模型支持类似物直接与NF-κB途径的元件相互作用的机制。总之，这些结果使SCFA-氨基己糖模板成为调节生物活性和开发新疗法的通用平台。
This study investigates the breadth of cellular responses engendered by short chain fatty acid (SCFA)-hexosamine hybrid molecules, a class of compounds long used in ‘metabolic glycoengineering’ that are now emerging as drug candidates. First, a ‘mix-and-match’ strategy showed that different SCFA (n-butyrate and acetate) appended to the same core sugar altered biological activity, complementing previous results [Campbell et al., (2008) J. Med. Chem. 51, 8135–8147] where a single type of SCFA elicited distinct responses. Microarray profiling then compared transcriptional responses engendered by regioisomerically-modified ManNAc, GlcNAc, and GalNAc analogs in MDA-MB-231 cells. These data – which were validated by qRT-PCR or Western analysis for ID1, TP53, HPSE, NQO1, EGR1 and VEGFA – showed a two-pronged response where a core set of genes was coordinately regulated by all analogs while each analog simultaneously uniquely regulated a larger number of genes. Finally, AutoDock modeling supported a mechanism where the analogs directly interact with elements of the NF-κB pathway. Together, these results establish the SCFA-hexosamine template as a versatile platform for modulating biological activity and developing new therapeutics.
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影响因子：
64.5
作者：
Lau, Ken S.;Partridge, Emily A.;Dennis, James W.
通讯作者：
Dennis, James W.
影响因子：
7.3
作者：
Campbell CT;Aich U;Weier CA;Wang JJ;Choi SS;Wen MM;Maisel K;Sampathkumar SG;Yarema KJ
通讯作者：
Yarema KJ
影响因子：
8
作者：
Hui, L.;Zheng, Y.;Foster, D. A.
通讯作者：
Foster, D. A.
影响因子：
2.9
作者：
Kim, EJ;Jones, MB;Yarema, KJ
通讯作者：
Yarema, KJ
影响因子：
3.6
作者：
Korashy, Hesham M.;El-Kadi, Ayman O. S.
通讯作者：
El-Kadi, Ayman O. S.