DRUG DISCOVERY FOR MICROSPORIDIAL INFECTIONS

艾滋病患者对机会性感染的易感性是 爱滋病的特点，并对其发病率和 死亡率。因此，通常是良性的无处不在的有机体变成了 免疫抑制个体的致衰性病原体。在这些人中 在艾滋病患者中问题尤其严重的物种是 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，目前还没有被证实有效的药物来对抗这些 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， 对治疗微孢子虫病有用的有效药物 疾病。为了帮助实现这一目标，这个项目的具体目标 项目是设计和合成化合物，这些化合物将选择性地 抑制微孢子虫的生长和繁殖，宿主最少 毒性。基于对这些生物不寻常的生命周期的了解 生物体，特别是关于极地的生物化学信息 构成生殖性和感染性的细丝结构 过程中，我们提出了一个基于结构和机制的方案来开发 会损害微孢子虫这一关键方面的药物 新陈代谢。具体地说，我们提出了几系列选择性微管蛋白 结合配体，因为微管蛋白对正常的极管功能和 孢子萌发。这些1-去氮蝶啶类似物和相关化合物 是为降低哺乳动物微管蛋白的亲和力而设计的。的活动 我们的先导化合物验证了这种方法。

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.