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

描述(由申请人提供)：糖原合成酶-3作为治疗布鲁氏锥虫的药物靶标非洲昏睡病是一种寄生虫病，在非洲困扰着多达50万人，通常会造成致命后果。需要新的疗法来治疗由布鲁氏锥虫引起的非洲昏睡病。糖原合成酶-3是一种存在于许多真核生物中的关键的激活酶。在初步数据中，我们发现：1)抑制布氏毛滴虫GSK-3的表达导致体外细胞生长停滞；2)GSK-3抑制剂导致布氏毛滴虫生长停滞和细胞死亡，其抗细胞活性与其对GSK-3酶的活性相关。尽管GSK-3抑制剂可以杀死布氏毛滴虫，但即使长期给药，特定的GSK-3抑制剂似乎对哺乳动物也没有毒性。因此，GSK-3是开发治疗布氏毛滴虫感染药物的极佳靶点。这项申请的总体目的是为了更好地了解布氏锥虫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(“Hit to Lead”开发)；将测试新合成的化合物对布氏锥虫GSK-3和细胞VS、哺乳动物激酶和细胞的比活性，以提高效力和特异性；2)使用布氏支原体GSK-3结构的模拟或求解布氏支原体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；3)通过修饰布氏毛滴虫中的GSK-3酶进一步验证靶标，使其被仅抑制修饰后的GSK-3酶的特殊分子所抑制。拥有只抑制布氏毛滴虫GSK-3的抑制剂是了解GSK-3抑制布氏毛滴虫生物学和药理作用的关键。在该项目结束时，我们将获得有关用于治疗非洲昏睡病的GSK-3抑制剂的关键信息，并将开发出2至3种先导化合物，以促进作为潜在疗法的优化。公共卫生意义：糖原合成酶-3作为治疗布氏锥虫的药物靶点本项目旨在研究糖原合成酶-3作为治疗布氏锥虫的可能药物靶点，并根据我们已发现的线索开发新药。引起非洲睡眠病的布鲁氏毛滴虫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，其中大多数最终导致死亡。现有的治疗布氏毛滴虫感染的药物毒性很大，其中一些药物仅治疗一项就会导致高达5%的死亡率。治疗这种感染的新药显然是需要的。

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.