Prenyl Diphosphate Synthase Inhibitors

描述（由申请人提供）：本研究的总体目标是 开发新的化疗方法来治疗非洲睡眠 南美锥虫病（南美锥虫病）和 利什曼病第一个目标是合成酶的抑制剂 法呢基焦磷酸合酶（FPPS）和香叶基香叶基焦磷酸合酶 （GGPPS），甲羟戊酸（异戊二烯）途径的关键酶。假设是 测试的是双膦酸盐和相关化合物是 FPPS和GGPPS酶，它们代表了新的抗寄生虫剂。的 这项工作的基本原理是，我们发现许多二磷酸盐抑制 寄生原虫T. cruzi，T. brucei rhodesiense，L. mexicana和L. donovani和效果寄生虫治疗L. Mexicana amazonensis和L. Balb/c小鼠的杜氏感染， 寄生虫血症T.克鲁兹FPPS已被确定为药物之一 目标和表达的T. cruzi FPPS已被证明是有效抑制 双膦酸盐，包括目前用于骨吸收治疗的那些。 第二个目的是测试基于膦酸酯的药物的抗寄生虫活性 并将这些信息用于药物设计。药物会 测试针对来自T. cruzi和T.布鲁氏菌和 L.的GGPPS。主要用于已建立的体外筛选系统和动物 利什曼病模型以及T. brucei和T.克鲁兹感染。的 第三个目标是优化双膦酸盐药物作为抗寄生虫药物的使用 通过与甲羟戊酸途径的其它抑制剂联合治疗的药物 以及优化药物递送（脂质体、聚合物和前体药物方法）， 从而导致更有效和/或更实用的疗法。

DESCRIPTION (provided by applicant): The overall objective of this research is to develop new chemotherapeutic approaches to the treatment of African sleeping sickness, South American trypanosomiasis (Chagas' disease) and the leishmaniases. The first aim is to synthesize inhibitors of the enzymes farnesyl pyrophosphate synthase (FPPS) and geranylgeranylpyrophosphate synthase (GGPPS), key enzymes of the mevalonate (isoprene) pathway. The hypotheses to be tested are that bisphosphonates and related compounds are inhibitors of the FPPS and GGPPS enzymes and they represent novel anti-parasitic agents. The rationale for this work is that we have found that many bisphosphates inhibit the growth of the parasitic protozoa T. cruzi, T. brucei rhodesiense, L. mexicana, and L. donovani and effect parasitological cures of L. mexicana amazonensis and L. donovani infections in Balb/c mice and 90 percent reductions in parasitemia with T. cruzi. FPPS has been identified as one of the drug targets and an expressed T. cruzi FPPS has been shown to be potently inhibited by bisphosphonates, including those currently used in bone resorption therapy. The second aim is to test the antiparasitic activity of phosphonate based drugs in vitro and in vivo and use this information for drug design. The drugs will be tested for activity against recombinant FPPS from T. cruzi and T. brucei and GGPPS of L. major, in established in vitro screening systems and in animal models of leishmaniasis, as well as T. brucei and T. cruzi infections. The third aim is to optimize the use of bisphosphonate drugs as antiparasitic agents via combination therapy with other inhibitors of the mevalonate pathway and to optimize drug delivery (liposomal, polymer and pro-drug approaches), leading to more efficient and/or more practical therapies.