Discovery of therapeutics against Cryptococcosis by Repurposing Pharmaceutical Libraries
Discovery of therapeutics against Cryptococcosis by Repurposing Pharmaceutical Libraries
批准号:
10308245
负责人:
HONGMIN LI
金额:
$16.14万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-02-01 至 2023-01-31
中文摘要
摘要:隐球菌感染引起的隐球菌病。C. neoformans和C. gatii遗迹
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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依托单位:
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