Prenyl Diphosphate Synthase Inhibitors

异戊二烯二磷酸合酶抑制剂

• 批准号: 6459345
• 负责人: Eric Oldfield
• 金额: $ 31.59万
• 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/6459345
• 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）：这项研究的总体目的是 开发新的化学治疗方法来治疗非洲睡眠 疾病，南美锥虫病（查加斯病）和 利什曼尼斯。第一个目的是合成酶的抑制剂 Farnesyl焦磷酸合酶（FPPS）和黄烷基戊基磷酸合酶合酶 （GGPPS），甲戊酸（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抑制剂 FPP和GGPPS酶，它们代表了新型的抗寄生虫。这 这项工作的理由是，我们发现许多双磷酸盐抑制了 Brucei Rhodesiense，L。寄生虫原生动物T. Cruzi的生长。 墨西哥和L. donovani以及墨西哥。 BALB/C小鼠中的Amazonensis和L. donovani感染和减少90％ 在寄生虫中与T. Cruzi。 FPP已被确定为其中一种药物 靶标和表达的Cruzi FPP已被证明是有效抑制的 通过双膦酸盐，包括目前用于骨吸收疗法的双膦酸盐。 第二个目的是测试磷酸药物的抗寄生虫活性 体外和体内，并将这些信息用于药物设计。毒品会 测试来自T. Cruzi和T. Brucei的重组FPP的活性 L. major的GGPP，在已建立的体外筛查系统和动物中 利什曼病的模型，以及T. Brucei和T. Cruzi感染。这 第三个目的是优化双膦酸盐药物作为抗寄生虫 通过组合疗法与甲戊酸途径的其他抑制剂组合疗法的代理 并优化药物输送（脂质体，聚合物和促毒方法）， 导致更有效和/或更实际的疗法。