DRUG DISCOVERY FOR MICROSPORIDIAL INFECTIONS

治疗微孢子虫感染的药物发现

• 批准号: 2672863
• 负责人: JOSEPH A MADDRY
• 金额: $ 22.24万
• 依托单位: SOUTHERN RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2672863
• 关键词: Microsporidia; antiprotozoal agents; binding proteins; cooperative study; drug design /synthesis /production; microorganism metabolism; tubulin

The susceptibility of AIDS patients to opportunistic infections is the distinguishing feature of AIDS and is responsible for its morbidity and mortality. Thus, ubiquitous organisms that are ordinarily benign become debilitating pathogens in the immunosuppressed individual. Among the species that have become especially problematic in AIDS patients are the unique protozoal microsporidia, obligate intracellular parasites that are now recognized as common causes of a variety of severe, chronic conditions. Unfortunately, despite the prevalence of microsporidial infections, there are no proven effective drugs available to combat these organisms or alleviate the associated symptoms. The overall goal of this Drug Discovery Group is the development of novel, effective agents that will be useful for the treatment of microsporidial disease. To help achieve this objective, the specific goal of this project is the design and synthesis of compounds that will selectively inhibit the growth and reproduction of microsporidia, with minimal host toxicity. Based on knowledge of the unusual life cycle of these organisms, and in particular, on biochemical information about the polar filament structure that underlies both the reproductive and infectious process, we propose a structure- and mechanism-based program to develop agents that will compromise this critical aspect of microsporidial metabolism. Specifically, we propose several series of selective tubulin binding ligands, since tubulin is vital to proper polar tube function and spore germination. These 1-deazapteridine analogs and related compounds are designed for reduced affinity for mammalian tubulin. The activity of our lead compounds validates this approach.

艾滋病患者对机会性感染的易感性是 艾滋病的一个显著特征，并导致其发病率， mortality. 因此，普遍存在的通常是良性的生物体变得 使免疫抑制个体虚弱的病原体。 中 在艾滋病患者中特别成问题的是 独特的原生动物微孢子虫，专性细胞内寄生虫， 现在被认为是各种严重、慢性 条件 不幸的是，尽管微孢子虫的流行 感染，没有被证明有效的药物可以对抗这些感染。 或减轻相关症状。 这个药物发现小组的总体目标是开发新的， 可用于治疗微孢子虫病的有效药剂 疾病 为了帮助实现这一目标， 该项目是设计和合成的化合物，将选择性地 抑制微孢子虫的生长和繁殖， 毒性 基于对这些不寻常的生命周期的了解， 生物，特别是关于极地生物的生物化学信息， 丝状结构是生殖和传染的基础 过程中，我们提出了一个结构和机制为基础的计划，以发展 会危害微孢子虫的这一关键方面的药剂 新陈代谢. 具体来说，我们提出了几个系列的选择性微管蛋白 结合配体，因为微管蛋白对适当的极管功能至关重要， 孢子萌发 这些1-脱氮杂哌啶类似物和相关化合物 被设计用于降低对哺乳动物微管蛋白的亲和力。 的活性 我们的先导化合物验证了这种方法。