Prenyl Diphosphate Synthase Inhibitors

异戊二烯二磷酸合酶抑制剂

• 批准号: 6622937
• 负责人: Eric Oldfield
• 金额: $ 31.57万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6622937
• 关键词: Leishmania major; Trypanosoma brucei rhodesiense; Trypanosoma cruzi; alkyltransferase; antiprotozoal agents; chemical registry /resource; deprenyl; drug design /synthesis /production; drug screening /evaluation; enzyme inhibitors; geranyl compound; laboratory mouse; leishmaniasis; microorganism disease chemotherapy; molecular cloning; phosphonate; pyrophosphates; trypanosomiasis

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.

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问题 病、南美锥虫病（恰加斯病）和 利什曼病。第一个目标是合成酶抑制剂 法尼基焦磷酸合酶 (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 经测试，双膦酸盐和相关化合物是 FPPS 和 GGPPS 酶是新型抗寄生虫药物的代表。这 这项工作的基本原理是我们发现许多二磷酸盐抑制 寄生原生动物 T. cruzi、T. brucei rhodesense、L. 的生长 墨西哥和 L. donovani 以及墨西哥 L. mexicana 的寄生虫治疗效果 Balb/c 小鼠的亚马逊和杜氏乳杆菌感染减少 90% 患有克氏锥虫寄生虫血症。 FPPS已被确定为药物之一 靶标和表达的克氏锥虫 FPPS 已被证明被有效抑制 双磷酸盐，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盐的药物的抗寄生虫活性 体外和体内，并使用这些信息进行药物设计。药物会 测试针对来自 T. cruzi 和 T. brucei 的重组 FPPS 的活性， L. Major 的 GGPPS，在已建立的体外筛选系统和动物中 利什曼病以及布氏锥虫和克氏锥虫感染的模型。这 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他抑制剂联合治疗的药物 并优化药物输送（脂质体、聚合物和前药方法）， 导致更有效和/或更实用的疗法。