Discovery of therapeutics against Cryptococcosis by Repurposing Pharmaceutical Libraries

通过重新利用药物库发现隐球菌病的治疗方法

• 批准号: 10308245
• 负责人: HONGMIN LI
• 金额: $ 16.14万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308245
• 关键词: Discovery; therapeutics; against; Cryptococcosis; Repurposing

Abstract: Cryptococcosis caused by infections of Cryptococcus spp. fungi. C. neoformans and C. gattii remains a leading killer of people living with HIV and post-organ transplant status. Recent outbreaks of infections of C. gattii in immune competent people raise significant concerns about the overall threat of cryptococcal species to public health. Cryptococcosis is one of the most difficult infections to treat with a mortality rate over 50%. New therapies with novel mechanism of actions (MOAs) are urgently needed to treat the infected. High throughput screening of target-based pharmaceutical libraries represents a very promising strategy to discover antifungals with novel MOAs because these libraries harbor well-defined molecules/compounds with desirable physicochemical properties, often with existing preclinical data for other therapeutic indications. Therefore, once identified, they can be quickly developed for novel applications such as antifungal. Cryptococcal fungi contain protein self-splicing elements, called inteins, in the essential gene, Prp8. Because inteins do not exist in multi- cellular organisms, such as humans, and often disrupt the functions of critical microbial genes, they are attractive drug targets. We have developed high throughput screening (HTS) strategies to allow identification of the Prp8 intein splicing inhibitors. In our preliminary results, we identified a few small molecule inhibitors that can inhibit the Prp8 intein splicing in vitro and inhibit the cryptococcosis in vivo. In this application, we will use our well- developed HTS assays to screen the predefined and target-based pharmaceutical libraries at the ICCB- Longwood screening facilities at the Harvard Medical School to identify the Prp8 intein splicing inhibitors. The identified candidate inhibitors will be characterized and optimized both in vitro and in vivo with the final aim to develop them as novel therapeutics for cryptococcosis.

翻译后摘要：隐球菌属感染引起的隐球菌病。真菌C.新型隐球菌和加蒂遗迹 艾滋病病毒感染者和器官移植后状态的主要杀手。近年来爆发的C. gattii在免疫能力正常的人提出了显着的关注隐球菌物种的整体威胁， 公共卫生隐球菌病是最难治疗的感染之一，死亡率超过50%。新 迫切需要具有新作用机制（MOA）的疗法来治疗感染者。高通量 筛选靶向药物库是发现抗真菌药物的一个非常有前途的策略 因为这些库含有具有期望的分子/化合物的明确定义的分子/化合物， 理化性质，通常与其他治疗适应症的现有临床前数据相结合。因此一旦 一旦被鉴定，它们就可以迅速开发用于新的应用，如抗真菌。隐球菌真菌含有 蛋白质自我剪接元件，称为内含肽，在必需基因Prp8中。因为内含肽不存在于多- 细胞生物，如人类，并且经常破坏关键微生物基因的功能，它们是有吸引力的 药物靶点我们已经开发了高通量筛选（HTS）策略，以允许识别Prp8 内含肽剪接抑制剂。在我们的初步结果中，我们确定了一些小分子抑制剂， Prp8蛋白内含肽在体外的剪接和在体内对隐球菌的抑制作用。在这个应用程序中，我们将使用我们的好- 开发了HTS检测试剂盒，以筛选ICCB的预定义和基于目标的药物库- 在哈佛医学院的Longwood筛选设施中鉴定Prp8内含肽剪接抑制剂。的 鉴定的候选抑制剂将在体外和体内进行表征和优化， 将其开发为隐球菌病的新疗法。