Drug development of orally active anti-trypanosomiasis agents

描述（由申请人提供）：非洲锥虫病，又称昏睡病，是一种由布鲁氏锥虫引起的媒介传播的寄生虫病。它威胁着撒哈拉以南非洲36个国家的6000多万人，这些国家的卫生系统效率最低，甚至根本没有卫生系统。目前还没有有效的疫苗和令人满意的治疗药物，迫切需要开发针对该疾病的新药。锥虫感染现在被称为“最被忽视的疾病”，需要更多的研究工作。微管在寄生虫细胞分裂和鞭毛运动中起着至关重要的作用。细胞分裂和运动对锥虫的生存至关重要。因此，微管蛋白抑制剂有望成为抗锥虫病药物，因为它们干扰微管动力学并抑制锥虫细胞分裂和细胞运动。微管蛋白是抗锥虫药物开发中公认的分子靶点。另一方面，微管蛋白也是开发抗癌药物的成熟分子靶点。临床上许多微管蛋白抑制剂是癌症治疗的首选化疗药物。然而，这些微管蛋白抑制剂对锥虫细胞生长的抑制活性非常弱，因为锥虫与哺乳动物的微管蛋白存在明显的差异。目前的任务是开发只干扰锥虫细胞的选择性微管蛋白抑制剂。我们从最初作为抗癌药物开发的微管蛋白抑制剂文库中发现了几种选择性降低锥虫细胞活力的先导化合物。基于这些化合物的抗锥虫细胞活性，总结了它们的构效关系。微管蛋白抑制剂对哺乳动物细胞生长抑制作用增强的药效团与对寄生虫生长抑制作用增强的药效团不同。这些结果鼓励我们期待在初步SAR的基础上可以开发出更多选择性和强效的抗锥虫病微管蛋白抑制剂。为了验证这一假设，我们将重点研究以下三个目标：1)优化先导化合物，以产生更多选择性和强效的抗锥虫病微管蛋白抑制剂。我们将使用药物化学方法来设计和合成新的类似物，并用锥虫和人类细胞生长试验来测试化合物。毒性更小的更有效的化合物将被发现。2)测定所选化合物的微管蛋白聚合抑制活性。我们将使用最初从哺乳动物和锥虫细胞中分离的微管蛋白来测试候选药物的蛋白质选择性。3)测定候选药物的体内抗锥虫活性和生物利用度。测定候选药物的口服活性和血脑屏障通过能力

DESCRIPTION (provided by applicant): African trypanosomiasis, also known as sleeping sickness, is a vector-borne parasitic disease caused by Trypanosoma brucei. It threatens over 60 million people in 36 countries of sub-Saharan Africa where health systems are least effective, or even non-existent. There are no effective vaccines and satisfactory drugs for the treatment, and the development of new drugs for the disease is urgently needed. Trypanosome infections are now referred as 'most neglected diseases', and need more research efforts. Microtubules are very critical for the parasite cell division as well as flagellar motility. Cellulr division and locomotion are essential for the trypanosome survival. Therefore, tubulin inhibitors are expected to be promising anti-trypanosomiasis agents, since they interfere with microtubule dynamics and suppress both trypanosome cell division and cell movement. Tubulin is a well-recognized molecular target for anti- trypanosome drug development. On the other hand, tubulin is also a mature molecular target for anti- cancer drug development. Many tubulin inhibitors are first chemotherapy for cancer treatment in clinic. However, these tubulin inhibitors show very weak inhibitory activity to the trypanosome cell growth, because there are clear differences between trypanosome and mammalian tubulin. Currently, the task is to develop selective tubulin inhibitors only interfering with trypanosome cells. We identified several lead compounds selectively decreasing trypanosome cell viability from a tubulin inhibitor library initially develoed as anti-cancer agents. A structure-activity relationship (SAR) was summarized based on the anti-trypanosome cell activity of these compounds. The pharmacophore of the tubulin inhibitors enhancing the mammalian cell growth inhibition was different to the pharmacophore promoting the parasite growth inhibition. The results encourage us to expect that more selective and potent tubulin inhibitors against trypanosomiasis could be developed based on the preliminary SAR. To test the hypothesis, we will focus on three research aims listed below: 1) Optimize the lead compounds to generate more selective and potent tubulin inhibitors against trypanosomiasis. We will use medicinal chemistry approaches to design and synthesize new analogs, and test the compounds with trypanosome and human cell growth assays. More potent compounds with lesser toxicity will be identified. 2) Determine the tubulin polymerization inhibitory activity of the selected compounds. We will use tubulin proteins originally isolated fro mammalian and trypanosome cells to test the protein selectivity of the drug candidates. 3) Determine the in vivo anti-trypanosome activity and the bioavailability of the drug candidates. The oral activity and blood brain barrier passing ability of the drug candidates will be determined with animals.