GLYCOSYLTRANSFERASE INHIBITORS AS ANTIFUNGAL AGENTS

作为抗真菌剂的糖基转移酶抑制剂

• 批准号: 2883827
• 负责人: NATHANIEL S. FINNEY
• 金额: $ 13.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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/2883827
• 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

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学中起着至关重要的作用。 感染性真菌的。几丁质合成酶（CS）是负责几丁质合成的酶 因此，CS是这些生物体的共同特征。的 酶在脊椎动物中不存在，并且代表了一个有吸引力的靶点， 寄生虫病的选择性服务治疗干预。的 有效CS抑制剂的成功开发将应用于 许多广泛传播的人类疾病，并将代表一种普遍的方法， 抑制其他生物学相关的进行性糖基转移酶。 提出的开发新CS抑制剂的方法基于两个 最近的发展。第一个是 疏水聚类分析（HCA）作为一种被广泛使用和接受的 用于识别蛋白质之间的结构相似性的计算方法 已知的基因序列。一些进行性糖基的HCA 转移酶如几丁质合成酶表明它们处理两个等价物， 糖的同时。这反过来表明，双底物类似物 其模拟UDP-GlcNAc的两个等价物，这应该将CS与 许多哺乳动物UDP-GlcNAc依赖性糖基转移酶。 这项建议所依赖的第二项发展是收集 技术进步通常被称为组合化学。这套 技术使得可以考虑并行合成， 筛选数百或数千个潜在的引线结构，而不是 通过传统方法连续合成更少量的化合物。 在目前的情况下，对这种酶知之甚少， 综合提供了提出数千个问题的机会（每个问题 由分子表示）关于活性位点的结构 同步如果问题池选择得当， 可以快速鉴定CS的高亲和力配体。这一进程将 同时提供关于酶的机理信息， 方法抑制进行性糖基转移酶，并绘制 新的抑制剂和（最终）新的治疗剂的途径。