ANTIMICROSPORIDIAL DRUG DISCOVERY RESERACH

抗微孢子虫药物发现研究

• 批准号: 6534204
• 负责人: JOSEPH A MADDRY
• 金额: $ 35.8万
• 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 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6534204
• 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，普遍存在的通常是良性的生物体变成了使人衰弱的病原体。 在艾滋病患者中变得特别成问题的物种中，并且在其他人群中越来越多地被诊断出的是独特的微孢子虫，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，但还没有经过证实的有效药物来对抗这些生物体或缓解相关症状。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所的药物化学家合作完成的。RO 1申请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，该项目的具体目标是双重的：设计和合成化合物，将有效地抑制微孢子虫的生长和复制，具有最小的宿主毒性;和先进的检测和模型的开发，以评估这些和其他药物，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程序，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剂。具体而言，我们提出了几个系列的杂环微管蛋白配体，相关的3-脱氮嘌呤和1-脱氮杂哌啶，已证明良好的抗微孢子虫体外疗效（见C节）。 我们还建议在适当的情况下将这些化合物的合成适应于更有效的组合方法，并进一步开发我们的体外和体内测定和模型。