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

描述（由申请人提供）：糖原合成酶激酶-3作为布鲁氏锥虫非洲昏睡病的药物靶点是一种寄生虫病，在非洲折磨着多达50万人，通常具有致命的后果。由布鲁氏锥虫引起的非洲昏睡病需要新的治疗方法。糖原合成酶激酶-3是许多真核生物中发现的一种关键激酶。在初步数据中，我们已经表明：1)抑制布鲁氏体GSK-3的表达导致体外细胞生长停滞；2) GSK-3抑制剂导致布鲁氏体生长停滞和细胞死亡，其对细胞的活性与其对GSK-3酶的活性相关。虽然GSK-3抑制剂能杀死布鲁氏体，但即使长期给药，特异性GSK-3抑制剂对哺乳动物也没有毒性。因此，GSK-3是开发治疗布鲁氏杆菌感染药物的一个极好的靶点。该应用程序的总体目的是更好地了解布鲁氏T. 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抑制剂作为非洲昏睡病的潜在药物（“先打后导”开发）；新合成的化合物将对布鲁氏体GSK-3和细胞、哺乳动物激酶和细胞进行特异性活性测试，以提高效力和特异性；2)利用对布鲁氏霉GSK-3结构的建模或求解布鲁氏霉GSK-3结构，利用基于结构的药物开发来指导SA #1中化合物的合成，帮助提高化合物的效价；3)通过修饰布鲁氏体寄生虫中的GSK-3酶，使其被只抑制修饰GSK-3酶的特殊分子所抑制，进一步验证了靶点。获得仅抑制布氏体GSK-3的抑制剂是了解GSK-3抑制布氏体寄生虫生物学和药理作用的关键。在该项目结束时，我们将获得用于治疗非洲昏睡病的GSK-3抑制剂的关键信息，并将开发2至3种先导化合物，以作为潜在的治疗药物进行优化。本项目旨在研究糖原合成酶激酶3作为布鲁氏锥虫可能的药物靶点，并在此基础上开发新的药物。引起非洲昏睡病的布氏体感染具有重要的公共卫生意义，因为据估计每年在非洲造成30万至50万例感染，其中大多数死亡。治疗布氏杆菌感染的现有药物毒性很大，其中一些药物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.