GLYCOSYLTRANSFERASE INHIBITORS AS ANTIFUNGAL AGENTS

描述：甲壳素在绝大多数人的生理中起着至关重要的作用。 感染性真菌。甲壳素合成酶(CS)是负责甲壳素的酶 生物合成，因此CS是将这些生物联系在一起的一个共同点。这个 酶在脊椎动物中是不存在的，是一个有吸引力的靶标 寄生虫病的选择性服务治疗干预。这个 一种有效的CS抑制剂的成功开发将在 一些广泛传播的人类疾病，并将代表着一种普遍的方法 抑制其他生物相关的前驱糖基转移酶。 开发新的CS抑制剂的建议方法是基于两个 相对较新的发展。其中第一个是出现了 疏水聚类分析(HCA)作为一种被广泛使用和接受的方法 识别蛋白质间结构相似性的计算方法 已知的基因序列。Hca中的一些顺式糖基 转移酶，如甲壳素合成酶，表明它们处理两个等价物 同时添加UDP-糖。这反过来又表明，双取代类似物 它模仿了UDP-GlcNAc的两个等价物，应该可以区分CS和 多种哺乳动物UDP-GlcNAc依赖的糖基转移酶。 这项提议所依赖的第二个发展是收集 通常被称为组合化学的技术进步。这套 技术使得考虑并行综合和 筛选数百或数千种潜在的铅结构，而不是 用传统方法连续合成数量少得多的化合物。 在目前对这种酶知之甚少的情况下，组合 综合提供了提出数千个问题(每个问题)的机会 由分子表示)关于活性中心的结构 同时。如果问题池选择得很好，它将是 有可能快速确定CS的高亲和力配体。这一过程将 同时提供有关酶的机理信息，定义一种通用的 探讨抑制过程性糖基转移酶，并绘制 通向新的抑制剂和(最终)新的治疗药物的道路。

DESCRIPTION: Chitin plays a crucial role in the physiology of the vast majority of infectious fungi. Chitin synthase (CS) is the enzyme responsible for chitin biosynthesis, and CS is thus a common denominator uniting these organisms. The enzyme is absent in vertebrate animals, and represents an attractive target for selective service therapeutic intervention in parasitic diseases. The successful development of a potent CS inhibitor would have application to a number of wide-spread human ailments, and would represent a general approach to the inhibition of other biologically relevant processive glycosyl transferases. The proposed approach to the development of new CS inhibitors is based on two relatively recent developments. The first of these is the emergence of hydrophobic cluster analysis (HCA) as a widely-used and widely-accepted computational method for identifying structural similarities between proteins with known genetic sequences. HCA of a number of processive glycosyl transferases such as chitin synthase suggests that they process two equivalents of UDP-sugar simultaneously. This in turn suggests that bisubstrate analogs which mimic two equivalents of UDP-GlcNAc should distinguish CS from the numerous mammalian UDP-GlcNAc-dependent glycosyl transferases. The second development upon which this proposal relies is the collection of technical advances commonly referred to as combinatorial chemistry. This set of techniques has made it possible to consider the parallel synthesis and screening of hundred or thousands of potential lead structures rather than the serial synthesis of a much smaller number of compounds by traditional methods. In the present case, where very little is known about the enzyme, combinatorial synthesis offers the opportunity to ask thousands of questions (each represented by a molecule) about the structure of the active site simultaneously. Provided the pool of questions is well chosen, it will be possible to rapidly identify high affinity ligands for CS. This process will simultaneously provide mechanistic information about enzyme, define a general approach to the inhibition of processive glycosyl transferases, and chart the path towards new inhibitors and (eventually) new therapeutic agents.