Rational Development of Anti-Trypanosoma Cruzi Drugs

描述（由申请人提供）：本研究项目的总体目标是发现可以开发成治疗南美锥虫病的药物的先导化合物。这种危及生命的疾病是由原生动物病原体克氏锥虫感染引起的。cruzi）。它在南美洲和中美洲流行，每年有超过1600万人慢性感染，约14,000人死亡。据信有超过10万美国公民受到感染。目前的治疗方案不足以治愈这种感染，因此需要研究以发现更好的化疗药物。该项目将集中于制备T. cruzi，甾醇14-脱甲基酶（Tc 14 DM）。这种酶是唑类抗真菌药物的靶点，是一个公认的抗菌靶点。我们假设，新的化合物可以合成与最佳的抗T。cruzi活性，这些将具有足够的活性来治愈患有慢性T.克氏感染我们提供了两个新的化学类，结合Tc 14 DM，并对T有效的活动的初步数据。克鲁兹文化具体目标是：1）合成潜在的替吡法尼类似物; cruzi化学疗法。替吡法尼是一种正在开发的用于癌症治疗的含咪唑化合物，具有优异的药代动力学特性。2)合成了一系列二取代咪唑类化合物作为潜在的T。cruzi化学疗法。初步数据显示，该系列产品具有较强的抗T。当口服给受感染的小鼠时，3)进行Tc 14 DM的分子建模和结构测定。基于原核CYP 51结构的分子模型最初将用于指导基于结构的药物设计。与此同时，将追求与抑制剂结合的酶的晶体结构，以帮助指导药物设计。4)建立Tc 14 DM的竞争结合试验。所提出的荧光偏振分析将有助于中高通量筛选化合物。5)测试化合物的功效、药代动力学和毒性。将采用一系列体外筛选，然后在小鼠模型中测试所选化合物。

DESCRIPTION (provided by applicant): The overall goal of this research project is to discover lead compounds that can be developed into therapeutics for treatment of Chagas disease. This life-threatening disease results from infection with the protozoan pathogen Trypanosoma cruzi (T. cruzi). It is endemic in South and Central America, with >16 million people chronically infected and approximately 14,000 deaths per year. More than 100,000 USA citizens are believed to be infected. Current treatment options are inadequate to cure this infection, thus research is needed to discover better chemotherapeutics. The project will focus on making inhibitors to a key enzyme involved in sterol biosynthesis in T. cruzi, sterol 14-demethylase (Tc14DM). This enzyme, the target of azole antifungal drugs, is a well established antimicrobial target. We hypothesize that new compounds can be synthesized with optimal anti-T. cruzi activity and these will be sufficiently active to cure animals (and humans) with chronic T. cruzi infection. We provide preliminary data on two new chemical classes that bind the Tc14DM and that have potent activity against T. cruzi cultures. The specific aims are: 1) Synthesize analogs of tipifarnib as potential T. cruzi chemotherapeutics. Tipifarnib is an imidazole- containing compound under development for cancer therapy and has excellent pharmacokinetic properties. 2) Synthesize a series of disubstituted imidazoles as potential T. cruzi chemotherapeutics. Preliminary data shows that this series has potent anti-T. cruzi activity when given orally to infected mice. 3) Perform molecular modeling and structure determination of Tc14DM. A molecular model based on a prokaryotic CYP51 structure will initially be utilized to guide structure-based drug design. Concomitantly, a crystal structure of the enzyme with bound inhibitors will be pursued to help guide drug design. 4) Develop a competition binding assay for Tc14DM. The proposed fluorescence polarization assay will assist moderate- to high-throughput screening of compounds. 5) Test compounds for efficacy, pharmacokinetics, and toxicity. A series of in vitro screens will be employed followed by testing selected compounds in mouse models.