ANTIMICROSPORIDIAL DRUG DISCOVERY RESERACH

艾滋病患者对机会性感染的易感性是该疾病的显著特征，并最终导致其发病率和死亡率。类似的机会性感染也困扰着其他免疫功能低下的个体，如移植患者和新生儿。因此，在免疫抑制的个体中，通常是良性的无所不在的生物体变成了使人衰弱的病原体。在艾滋病患者中已经成为特别问题的物种中，并且在其他人群中越来越多地被诊断出来，是独特的微孢子虫，专性细胞内寄生虫，现在被认为是各种严重慢性疾病的常见原因。不幸的是，尽管微孢子虫感染很普遍，但目前还没有证明有效的药物来对抗这些微生物或缓解相关症状。这个项目是杜兰大学和乔治·华盛顿大学的生物学家以及南方研究中心的药物化学家的合作项目。RO1应用的总体目标是开发可用于治疗微孢子虫病的新型有效药物。为了实现这一目标，该项目的具体目标有两个：设计和合成能够有效抑制微孢子虫生长和复制的化合物，同时使宿主毒性最小；开发先进的分析方法和模型来评估这些药物和其他药物，以帮助指导合成程序。基于对微孢子生物化学和生命周期的了解，我们提出了一个基于结构和机制的方案来开发通过抑制有丝分裂和极管挤压来破坏微孢子复制的药物。具体来说，我们提出了几个系列的杂环微管配体，与3-去氮杂嘌呤和1-去氮杂嘌呤相关，它们在体外表现出良好的抗孢子作用（见C部分）。我们还建议在适当的地方调整这些化合物的合成以更有效的组合方法，并进一步发展我们的体外和体内试验和模型。

The susceptibility of AIDS patients to opportunistic infections is the distinguishing feature of the disease, and is ultimately responsible for its morbidity and mortality. Similar opportunistic infections plague other immunocompromised individuals, such as transplant patients and neonates. 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, and that are diagnosed increasingly in other populations, are the unique 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 to combat these organisms or relieve the associated symptoms. This program is a collaboration between biologists at Tulane and George Washington, and medicinal chemists at Southern Research. The overall goal of the RO1 application is the development of novel, effective agents that will be useful for the treatment of microsporidial disease. To achieve this objective, the specific goals of this project are twofold: the design and synthesis of compounds that will effectively inhibit the growth and replication of microsporidia, with minimal host toxicity; and the development of advanced assays and models to evaluate these and other drugs, to help guide the synthetic program. Based on knowledge of microsporidial biochemistry and life cycle, we propose a structure- and mechanism-based program to develop agents that will undermine microsporidial replication through inhibition of mitosis and, possibly, polar tube extrusion. Specifically, we propose several series of heterocyclic tubulin ligands, related to 3-deazapurine and 1-deazapteridine, that have demonstrated good antimicrosporidial efficacy in vitro (see Section C). We also propose to adapt the synthesis of these compounds to more efficient combinatorial methods where appropriate, and to further develop our in vitro and in vivo assays and models.