Modular synthesis of heparan sulfate oligosaccharides for structure-activity relationship studies.
Modular synthesis of heparan sulfate oligosaccharides for structure-activity relationship studies.
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DOI：
10.1021/ja907358k
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发表时间：
2009-12-02
影响因子：
15
通讯作者：
Boons, Geert-Jan
中科院分区：
文献类型：
--
作者：
Arungundram, Sailaja;Al-Mafraji, Kanar;Asong, Jinkeng;Leach, Franklin E., III;Amster, I. Jonathan;Venot, Andre;Turnbull, Jeremy E.;Boons, Geert-Jan
尽管已经鉴定了数百种硫酸乙酰肝素结合蛋白，并且其涉及无数的生理和病理过程，但是关于这些蛋白结合和介导生物活性的配体要求的信息非常少。这种困难是由于缺乏建立结构-活性-关系的技术，这又是由于天然硫酸乙酰肝素（HS）的结构复杂性和制备定义明确的HS-寡糖的困难。为了解决这一缺陷，我们已经开发了一种模块化的方法，利用相对少量的选择性保护的二糖结构单元，可以很容易地转化为糖基供体和受体的平行组合合成HS寡糖。模块化构建块的效用已经通过制备十二种寡糖的文库来证明，所述寡糖已经用于探测HS用于抑制蛋白酶BACE-1的结构特征。活性与结构变化的复杂变化支持重要的功能信息嵌入在HS序列中的观点。此外，最具活性的衍生物为制备更有效的化合物提供了有吸引力的先导化合物，这些化合物可用作阿尔茨海默病的治疗剂。
Although hundreds of heparan sulfate binding proteins have been identified, and implicated in a myriad of physiological and pathological processes, very little information is known about ligand requirements for binding and mediating biological activities by these proteins. This difficulty results from a lack of technology for establishing structure-activity-relationships, which in turn is due to the structural complexity of natural heparan sulfate (HS) and difficulties of preparing well-defined HS-oligosaccharides. To address this deficiency, we have developed a modular approach for the parallel combinatorial synthesis of HS oligosaccharides that utilizes a relatively small number of selectively protected disaccharide building blocks, which can easily be converted into glycosyl donors and acceptors. The utility of the modular building blocks has been demonstrated by the preparation of a library of twelve oligosaccharides, which has been employed to probe structural features of HS for inhibiting the protease, BACE-1. The complex variations in activity with structural changes support the view that important functional information is embedded in HS sequences. Furthermore, the most active derivative provides an attractive lead compound for the preparation of more potent compounds, which may find use as a therapeutic agent for Alzheimer's disease.
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影响因子：
2.8
作者：
de Paz, JL;Martin-Lomas, M
通讯作者：
Martin-Lomas, M
影响因子：
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作者：
Chen, Chen;Yu, Biao
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Yu, Biao
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作者：
DAVIS, NJ;FLITSCH, SL
通讯作者：
FLITSCH, SL
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作者：
Gavard, O;Hersant, Y;Bonnaffé, D
通讯作者：
Bonnaffé, D
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作者：
Gama, Cristal I.;Tully, Sarah E.;Hsieh-Wilson, Linda C.
通讯作者：
Hsieh-Wilson, Linda C.