Prenyl Diphosphate Synthase Inhibitors

描述(申请人提供)：本研究的总体目标是 开发治疗非洲睡眠的新化疗方法 疾病，南美锥虫病(恰加斯病)和 利什曼病。第一个目标是合成酶的抑制剂。 法尼基焦磷酸合成酶和香叶基香叶基焦磷酸合成酶 甲氧丙戊酸(异戊二烯)途径的关键酶(GGPPS)。假设是 测试表明，双膦酸盐和相关化合物是 FFP和GGPPS酶，它们代表了新型的抗寄生虫剂。这个 这项工作的基本原理是，我们已经发现许多双磷酸盐抑制 对寄生原生动物克氏原虫、布氏原虫、罗德氏原虫、布氏原虫、罗德氏原虫的生长进行了研究。 墨西哥乳杆菌和多诺氏乳杆菌及其对墨西哥乳杆菌寄生治疗的影响 Balb/c小鼠感染亚马逊血吸虫和杜氏钩端螺旋体，减少率达90% 在克氏锥虫寄生虫病中。FFP已被确认为其中一种药物 靶标和表达的克氏锥虫FPS已被证明是有效的抑制 由双膦酸盐，包括目前用于骨吸收治疗的那些。 第二个目的是测试以膦为基础的药物的抗寄生虫活性。 在体外和体内，并利用这些信息进行药物设计。这些药物会 检测对克鲁兹毛滴虫和布氏毛滴虫重组FPPS的活性和 在建立体外筛选系统和动物体内的基础上 利什曼病模型，以及布氏毛滴虫和克鲁兹毛滴虫感染。这个 第三个目标是优化双膦酸类药物作为抗寄生虫药物的使用。 与甲氧戊酸途径的其他抑制剂联合治疗的药物 并优化药物传递(脂质体、聚合物和亲药物方法)， 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.