Cysteine protease inhibitors as chemotherapy for parasitic infections
Cysteine protease inhibitors as chemotherapy for parasitic infections
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DOI：
10.1016/s0968-0896(99)00008-5
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发表时间：
1999-04-01
影响因子：
3.5
通讯作者：
Caffrey, CR
中科院分区：
文献类型：
--
作者：
McKerrow, JH;Engel, JC;Caffrey, CR
对后生动物和原生动物寄生虫中木瓜蛋白酶家族半胱氨酸蛋白酶的进化、定位和生物学功能的分析为了解这一多样化酶家族的生物化学和细胞功能提供了重要且常常令人惊讶的见解。此外，与哺乳动物宿主相比，寄生虫中相对缺乏半胱氨酸蛋白酶冗余，这使得它们成为开发新的抗寄生虫化疗的有吸引力的目标。用半胱氨酸蛋白酶抑制剂治疗寄生虫病实验模型为半胱氨酸蛋白酶抑制剂在体内的使用提供了重要的“概念证明”。现在积累的证据表明，半胱氨酸蛋白酶抑制剂可以选择性地阻止微生物病原体的复制，而不会对宿主产生不良毒性。此外，这可以通过合理的给药方案和口服药物来实现。初步研究已证实半胱氨酸蛋白酶抑制剂在治疗克氏锥虫、恶性疟原虫和大型利什曼原虫方面的功效。对非洲锥虫病病原体布氏锥虫的研究尚处于初步阶段，但前景广阔。靶标验证研究表明，生物素化或放射性标记的不可逆抑制剂特异性结合半胱氨酸蛋白酶靶标，这些靶标被认为代表了寄生虫内的主要活性。就克氏锥虫而言，抑制剂的作用似乎主要是阻断蛋白酶加工。使用变体构建体的转染研究支持了该模型。最后，墨西哥利什曼原虫多个蛋白酶基因无效突变体的产生，为该酶家族在寄生虫毒力中的关键作用提供了第一个遗传支持。啮齿类动物的安全性研究以及寄生虫和宿主细胞对抑制剂摄取的分析表明，抑制剂对寄生虫靶点的选择性可能在于寄生虫蛋白酶缺乏冗余、细胞内宿主蛋白酶浓度较高以及寄生虫对抑制剂的摄取差异。在寄生虫培养物中引发对半胱氨酸蛋白酶抑制剂的抗性的尝试表明，诱导抗性的机制独立于对传统抗寄生虫药的抗性。这表明半胱氨酸蛋白酶抑制剂可能为耐药生物提供传统疗法的替代方案。 (C) 1999 Elsevier Science Ltd. 保留所有权利。
Analysis of the evolution, localization and biologic function of papain family cysteine proteases in metazoan and protozoan parasites has provided important and often surprising insights into the biochemistry and cellular function of this diverse enzyme family. Furthermore, the relative lack of redundancy of cysteine proteases in parasites compared to their mammalian hosts makes them attractive targets for the development of new antiparasitic chemotherapy. The treatment of experimental models of parasitic diseases with cysteine protease inhibitors has provided an important 'proof of concept' for the use of cysteine protease inhibitors in vivo. Evidence has now accumulated that cysteine protease inhibitors can selectively arrest replication of a microbial pathogen without untoward toxicity to the host. Furthermore, this can be achieved with reasonable dosing schedules and oral administration of the drug. Initial studies have confirmed the efficacy of cysteine protease inhibitors in treatment of Trypanosoma cruzi, Plasmodium falciparum and Leishmania major. Work on Trypanosoma brucei, the agent of African trypanosomiasis, is preliminary but also promising. Target validation studies have shown that biotinylated or radiolabeled irreversible inhibitors specifically bind to the cysteine protease targets thought to represent the major activity within the parasite. Tn the case of T. cruzi, the effect of inhibitors appears to be predominantly in blocking protease processing. Transfection studies using variant constructs have supported this model. Finally, the generation of null mutants for the multiple protease genes in Leishmania mexicana has provided the first genetic support for the key role of this enzyme family in parasite virulence. Safety studies in rodents and analysis of uptake of inhibitors by parasites and host cells suggest that the selectivity of inhibitors for the parasite targets may reside in the lack of redundancy of parasite proteases, the higher concentration of host proteases in intracellular compartments, and differential uptake of inhibitors by parasites. Attempts to elicit resistance to cysteine protease inhibitors in parasite cultures suggest that mechanisms of induced resistance are independent of resistance to the traditional antiparasitic agents. This suggests that cysteine protease inhibitors may provide an alternative to traditional therapy in drug-resistant organisms. (C) 1999 Elsevier Science Ltd. All rights reserved.