ANTIMICROSPORIDIAL DRUG DISCOVERY RESERACH

抗微孢子虫药物发现研究

• 批准号: 6647178
• 负责人: JOSEPH A MADDRY
• 金额: $ 43.23万
• 依托单位: SOUTHERN RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-15 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6647178
• 关键词: Microsporidia; athymic mouse; azapurine; benzimidazoles; benzodiazepines; cell cycle; combinatorial chemistry; diazepine; drug adverse effect; drug design /synthesis /production; drug discovery /isolation; drug interactions; drug screening /evaluation; enzyme linked immunosorbent assay; heterocyclic compounds; microorganism disease chemotherapy; microtubules; oxazoles; pteridine analog; tissue /cell culture; transmission electron microscopy; western blottings

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.

艾滋病患者对机会性感染的易感性是该病的显著特征，也是其发病率和死亡率的最终原因。类似的机会性感染困扰着其他免疫受损的人，如移植患者和新生儿。因此，无处不在的生物体通常是良性的，但在免疫抑制的个体中会成为衰弱的病原体。在艾滋病患者中变得特别有问题的物种中，有一种独特的微孢子虫，这种专性细胞内寄生虫现在被认为是各种严重、慢性疾病的共同原因，在其他人群中越来越多地被诊断出来。不幸的是，尽管微孢子虫感染盛行，但还没有被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与南方研究中心的药物化学家合作完成的。RO1应用的总体目标是开发对治疗微孢子虫病有用的新的、有效的药物。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，并将宿主毒性降至最低；开发先进的分析方法和模型来评估这些药物和其他药物，以帮助指导合成计划。基于微孢子虫生物化学和生命周期的知识，我们提出了一个基于结构和机制的计划，以开发通过抑制有丝分裂和可能的极管挤出来破坏微孢子虫复制的药物。具体地说，我们提出了几个与3-去氮嘌呤和1-去氮蝶啶相关的杂环微管蛋白配体，它们在体外显示了良好的抗微孢子虫效果(见C节)。我们还建议在适当的情况下将这些化合物的合成调整为更有效的组合方法，并进一步发展我们的体外和体内分析和模型。