Glycogen Synthase Kinase-3 as a drug target for Trypanosoma brucei

描述（由申请人提供）：糖原合酶激酶-3作为布氏锥虫非洲昏睡病的药物靶标，是一种寄生虫病，在非洲困扰多达50万人，通常具有致命的后果。由布氏锥虫引起的非洲嗜睡症需要新的治疗方法。糖原合成酶激酶-3是在许多真核生物中发现的关键激酶。在初步的数据中，我们已经表明：1）抑制T。布氏杆菌GSK-3表达导致体外细胞生长停滞; 2）GSK-3抑制剂导致T.它们对细胞的活性与它们对GSK-3酶的活性相关。GSK-3抑制剂虽然能杀死T.对于布氏杆菌，特异性GSK-3抑制剂即使长期给药对哺乳动物也没有毒性。因此，GSK-3是开发治疗T.布鲁氏菌感染。本申请的总体目的是为了更好地理解T.布鲁氏菌GSK-3，并利用这些信息开发针对GSK-3的先导化合物，用于治疗非洲昏睡病。该项目的目标包括：1）进一步开发小分子GSK-3抑制剂作为治疗非洲昏睡病的潜在药物（“命中领先”开发）;新合成的化合物将测试对T的特异性活性。布氏杆菌GSK-3和细胞与哺乳动物激酶和细胞的比较，以提高效力和特异性; brucei GSK-3结构或解决T.布氏杆菌GSK-3结构，并使用基于结构的药物开发来指导SA #1中化合物的合成，以帮助提高化合物的效力;以及3）通过修饰T.通过仅抑制修饰的GSK-3酶的专门分子来抑制布鲁氏菌寄生虫。有抑制T.因此，对布氏杆菌GSK-3的研究是理解GSK-3抑制对T.布鲁氏菌寄生虫在该项目结束时，我们将获得有关GSK-3抑制剂治疗非洲昏睡病的关键信息，并将开发2至3种先导化合物作为潜在的治疗药物进行优化。公共卫生相关性：糖原合成酶激酶-3作为布氏锥虫的药物靶点本项目旨在研究糖原合成酶激酶-3作为布氏锥虫的药物靶点。并根据我们发现的线索开发新药。引起非洲昏睡病的布氏杆菌感染具有公共卫生意义，因为据估计，它每年在非洲造成30万至50万人感染，其中大多数人死亡。现有的治疗T.布氏杆菌感染的毒性很强，其中一些仅通过治疗就可导致高达5%的死亡率。显然需要针对这种感染的新药。

DESCRIPTION (provided by applicant): Glycogen Synthase Kinase-3 as a drug target for Trypanosoma brucei African sleeping sickness is a parasitic disease afflicting up to 500,000 persons in Africa, often with fatal outcomes. New therapeutics are needed for African sleeping sickness, caused by Trypanosoma brucei spp. Glycogen synthase kinase-3 is a critical kinase enzyme found in many eukaryotic organisms. In preliminary data, we have shown that: 1) inhibition of T. brucei GSK-3 expression leads to in vitro cell growth arrest; and 2) inhibitors of GSK-3 lead to growth arrest and cell death of T. brucei and their activity against cells correlates with their activity against GSK-3 enzyme. Though GSK-3 inhibitors kill T. brucei, specific GSK-3 inhibitors do not appear toxic to mammals even with chronic administration. Thus, GSK-3 is an excellent target for developing drugs to treat T. brucei infections. The overall purpose of this application is to better understand T. brucei GSK-3 and use this information to develop lead compounds that target GSK-3 for the treatment of African sleeping sickness. The Aims of this project include: 1) Further develop small molecule GSK-3 inhibitors as potential drugs for African sleeping sickness ("hit to lead" development); newly synthesized compounds will be tested for specific activity against T. brucei GSK-3 and cells vs, mammalian kinases and cells to improve potency and specificity; 2) Use modeling of the T. brucei GSK-3 structure or solve the T. brucei GSK-3 structure and use structure-based-drug development to direct synthesis of compounds in SA #1 to help improve potency of the compounds; and 3) further validate the target by modifying GSK-3 enzyme in T. brucei parasites to be inhibited by specialized molecules that will only inhibit modified GSK-3 enzyme. Having inhibitors that only inhibit T. brucei GSK-3 is key to understanding the biological and pharmacological effects of GSK-3 inhibition on T. brucei parasites. At the end of this project, we will have critical information about GSK-3 inhibitors for the therapy of African sleeping sickness and will have developed 2 to 3 lead compounds to take forward for optimization as potential therapeutics. PUBLIC HEALTH RELEVANCE: Glycogen Synthase Kinase-3 as a drug target for Trypanosoma brucei this project is to investigate Glycogen Synthase Kinase-3 as a possible drug target for T. brucei and to develop new drugs based on the leads we have found. T. brucei infection, causing African Sleeping Sickness, is of public health significance because it is estimated to cause between 300,000 and 500,000 infections per year in Africa, most of which end fatally. The available drugs for T. brucei infection are very toxic, some of them causing up to 5% mortality from the therapy alone. New drugs for this infection are clearly needed.