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GLYCOSYLTRANSFERASE INHIBITORS AS ANTIFUNGAL AGENTS

作为抗真菌剂的糖基转移酶抑制剂

基本信息

批准号：
6642099
负责人：
NATHANIEL S. FINNEY
金额：
$ 12.41万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-08-01 至 2004-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6642099
关键词：
active sites antifungal agents chemical structure function chitin combinatorial chemistry drug design /synthesis /production drug screening /evaluation enzyme inhibitors glycosyltransferase microorganism disease chemotherapy mycosis peptide library

项目摘要

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.

描述：甲壳素在绝大多数人的生理机能中发挥着至关重要的作用的传染性真菌。几丁质合成酶 (CS) 是负责几丁质的酶因此，CS 是结合这些生物体的共同点。这脊椎动物中不存在这种酶，并且是一个有吸引力的目标寄生虫病的选择性服务治疗干预。这有效的 CS 抑制剂的成功开发将应用于一些广泛传播的人类疾病，并代表了治疗的一般方法抑制其他生物学相关的进行性糖基转移酶。所提出的开发新 CS 抑制剂的方法基于两个相对较新的发展。其中第一个是出现疏水聚类分析（HCA）作为一种广泛使用和广泛接受的方法识别蛋白质之间结构相似性的计算方法具有已知的基因序列。多个进行性糖基的 HCA 几丁质合酶等转移酶表明它们会处理两个等价物同时UDP-糖。这反过来表明双底物类似物它模仿了 UDP-GlcNAc 的两个等价物，应该将 CS 与许多哺乳动物 UDP-GlcNAc 依赖性糖基转移酶。该提案所依赖的第二个发展是收集技术进步通常称为组合化学。这一套技术使得考虑并行合成和筛选数百或数千个潜在的先导结构，而不是通过传统方法连续合成数量少得多的化合物。在目前的情况下，人们对酶知之甚少，组合综合提供了提出数千个问题的机会（每个问题由分子代表）关于活性位点的结构同时地。如果问题库选择得当，可以快速识别CS的高亲和力配体。这个过程将同时提供有关酶的机械信息，定义一般抑制进行性糖基转移酶的方法，并绘制图表通往新抑制剂和（最终）新治疗剂的道路。