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.

摘要： 隐球菌病是由隐球菌属感染引起的。真菌。新型隐球菌和格特隐球菌遗骸 艾滋病毒感染者和器官移植后状态的主要杀手。最近爆​​发的感染 C. 免疫能力强的人群中的 gattii 引起了人们对隐球菌物种对免疫系统的总体威胁的严重担忧。 公共卫生。隐球菌病是最难治疗的感染之一，死亡率超过 50%。新的 迫切需要具有新作用机制（MOA）的疗法来治疗感染者。高通量 基于靶点的药物库筛选是发现抗真菌药物的一种非常有前途的策略 具有新颖的 MOA，因为这些库包含明确定义的分子/化合物，具有所需的 理化特性，通常与其他治疗适应症的现有临床前数据一起。因此，一旦 一旦确定，它们就可以快速开发用于抗真菌等新应用。隐球菌真菌含有 蛋白质自剪接元件，称为内含肽，位于必需基因 Prp8 中。因为内含肽不存在于多种 细胞生物，例如人类，经常破坏关键微生物基因的功能，因此它们很有吸引力 药物靶点。我们开发了高通量筛选 (HTS) 策略来识别 Prp8 内含肽剪接抑制剂。在我们的初步结果中，我们鉴定了一些可以抑制 体外观察 Prp8 内含子剪接，体内抑制隐球菌病。在这个应用程序中，我们将使用我们的良好 开发了 HTS 测定法，以筛选 ICCB 中预定义的基于目标的药物库 哈佛医学院的 Longwood 筛选设施用于鉴定 Prp8 内含肽剪接抑制剂。这 确定的候选抑制剂将在体外和体内进行表征和优化，最终目标是 将它们开发为隐球菌病的新疗法。