Cysteine protease inhibitors cure an experimental Trypanosoma cruzi infection.
Cysteine protease inhibitors cure an experimental Trypanosoma cruzi infection.
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DOI：
10.1084/jem.188.4.725
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发表时间：
1998-08-17
期刊：
影响因子：
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通讯作者：
McKerrow JH
中科院分区：
文献类型：
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作者：
Engel JC;Doyle PS;Hsieh I;McKerrow JH
克氏锥虫是恰加斯病的病原体。主要的蛋白酶cruzain是开发新的化疗药物的靶点。我们报告了首次成功治疗恰加斯病的动物模型与抑制剂设计灭活cruzain。用氟甲基酮衍生的假肽治疗可使小鼠免于致命感染。最佳的假肽支架为苯丙氨酸-同苯丙氨酸。为了达到治愈感染的目的，将这种假肽支架掺入毒性较小的乙烯砜衍生物中。n -甲基哌嗪- ph -同质-乙烯基砜苯基也能使小鼠免于致命感染。接受治疗的小鼠中有6只存活了9个多月，其中3只没有接受进一步治疗。3只进入慢性感染阶段的小鼠以20 d的治疗方案进行治疗。实验结束时，6只小鼠中有5只血液培养反复阴性，表明寄生虫治愈。抑制剂对细胞内无纺锤体形式影响的研究表明，由于抑制剂在高尔基复合物水平上阻止正常的自蛋白水解cruzain加工，生命周期被中断。从接受治疗的小鼠心脏中恢复的寄生虫显示出与体外治疗的小鼠相同的异常。宿主细胞的高尔基复合体未见异常。本研究提供的概念证明，半胱氨酸蛋白酶抑制剂可以给予治疗剂量的动物选择性地阻止寄生虫感染。
Trypanosoma cruzi is the causative agent of Chagas' disease. The major protease, cruzain, is a target for the development of new chemotherapy. We report the first successful treatment of an animal model of Chagas' disease with inhibitors designed to inactivate cruzain. Treatment with fluoromethyl ketone–derivatized pseudopeptides rescued mice from lethal infection. The optimal pseudopeptide scaffold was phenylalanine-homophenylalanine. To achieve cure of infection, this pseudopeptide scaffold was incorporated in a less toxic vinyl sulfone derivative. N-methyl piperazine-Phe-homoPhe-vinyl sulfone phenyl also rescued mice from a lethal infection. Six of the treated mice survived over nine months, three without further treatment. Three mice that had entered the chronic stage of infection were retreated with a 20-d regimen. At the conclusion of the experiments, five of the six mice had repeated negative hemacultures, indicative of parasitological cure. Studies of the effect of inhibitors on the intracellular amastigote form suggest that the life cycle is interrupted because of inhibitor arrest of normal autoproteolytic cruzain processing at the level of the Golgi complex. Parasites recovered from the hearts of treated mice showed the same abnormalities as those treated in vitro. No abnormalities were noted in the Golgi complex of host cells. This study provides proof of concept that cysteine protease inhibitors can be given at therapeutic doses to animals to selectively arrest a parasitic infection.