In Vitro and In Vivo Investigation of the Inhibition of Trypanosoma brucei Cell Growth by Lipophilic Bisphosphonates.
In Vitro and In Vivo Investigation of the Inhibition of Trypanosoma brucei Cell Growth by Lipophilic Bisphosphonates.
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亲脂性双膦酸盐抑制布氏锥虫细胞生长的体外和体内研究。
DOI：
10.1128/aac.01873-15
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发表时间：
2015
影响因子：
4.9
通讯作者：
No,JooHwan
中科院分区：
文献类型：
--
作者：
Yang,Gyongseon;Zhu,Wei;Kim,Kuglae;Byun,SooYoung;Choi,Gahee;Wang,Ke;Cha,JeongSeok;Cho,Hyun-Soo;Oldfield,Eric;No,JooHwan
本文报道了从925个潜在的异戊烯基合酶抑制剂库中筛选布氏锥虫法呢基二磷酸合酶（TbFPPS）和T。布氏杆菌，非洲人类锥虫病的病原体。最有效的化合物是骨吸收药物唑来膦酸盐的亲脂性类似物，其中一些对血流形式T具有亚微摩尔至低微摩尔活性。布氏杆菌，选择性指数高达1000。我们评估了两种抑制剂对T.布氏小鼠感染模型，发现存活时间增加了16天。我们还研究了三个亲脂性的双膦酸盐的结合表达TbFPPS使用结晶学和研究的热力学结合使用等温滴定量热法。
We report the results of a screen of a library of 925 potential prenyl synthase inhibitors against Trypanosoma brucei farnesyl diphosphate synthase (TbFPPS) and against T. brucei, the causative agent of human African trypanosomiasis. The most potent compounds were lipophilic analogs of the bone resorption drug zoledronate, some of which had submicromolar to low micromolar activity against bloodstream form T. brucei and selectivity indices of up to ∼300. We evaluated the effects of two such inhibitors on survival and parasitemia in a T. brucei mouse model of infection and found that survival increased by up to 16 days. We also investigated the binding of three lipophilic bisphosphonates to an expressed TbFPPS using crystallography and investigated the thermodynamics of binding using isothermal titration calorimetry.