Protein kinases as targets for anti-parasitic chemotherapy
Protein kinases as targets for anti-parasitic chemotherapy
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DOI：
10.1016/j.bbapap.2003.11.021
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发表时间：
2004-03-11
影响因子：
3.2
通讯作者：
Doerig, C
中科院分区：
文献类型：
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作者：
Doerig, C
感染人类的寄生原生动物对公众健康产生惊人的影响，特别是在发展中国家。此外，一些原生动物物种是家畜的主要病原体，对粮食生产具有相当大的影响。在许多情况下，寄生虫已经对现有的化疗药物产生了耐药性，因此寻找替代药物成为当务之急。与当前人们对蛋白激酶抑制剂作为对抗多种疾病的潜在药物的兴趣一致，正在探索蛋白激酶可能代表新型抗寄生虫药物的靶标的可能性。寄生虫蛋白激酶的研究极大地受益于基因组和 EST 测序项目，一些物种的基因组已完全测序（特别是人类疟原虫恶性疟原虫的基因组），还有几个物种的基因组正在进行中。该领域研究的总体情况表明，寄生原生动物的系统发育分离反映在其许多蛋白激酶同源物的非典型结构和功能特性上。同样，越来越多的证据表明，一些原本保守的信号转导途径的组织在某些寄生物种中是不同的。寄生虫的蛋白激酶与其宿主细胞中的同源物之间的差异表明可以实现对前者的特异性抑制。基于蛋白激酶抑制的抗寄生虫药物的开发有两种途径：一是筛选重组酶的化学文库；二是筛选重组酶的化学文库。寄生原生动物的几种蛋白激酶现在可用于这种方法。第二种方法依赖于鉴定具有抗寄生虫特性的激酶抑制剂的分子靶标。这在一些情况下取得了有希望的进展，特别是 PKG 作为对抗艾美耳球虫和弓形虫的药物靶点，以及 purvalanol B（一种基于嘌呤的 CDK 抑制剂，它似乎会影响几种原生动物寄生虫中意想不到的靶点）。最近对与小抑制分子复合的疟原虫蛋白激酶结构的解析，为基于激酶抑制的抗寄生虫药物设计的合理方法开辟了道路。 (C) 2003 Elsevier B.V. 保留所有权利。
Parasitic protozoa infecting humans have a staggering impact on public health, especially in the developing world. Furthermore, several protozoan species are major pathogens of domestic animals and have a considerable impact on food production. In many instances, the parasites have developed resistance against available chemotherapeutic agents, making the search for alternative drugs a priority. In line with the current interest in protein kinases inhibitors as potential drugs against a variety of diseases, the possibility that protein kinases may represent targets for novel anti-parasitic agents is being explored. Research into parasite protein kinases has benefited greatly from genome and EST sequencing projects, with the genomes of a few species fully sequenced (notably that of the human malaria parasite Plasmodilum falciparum) and several more under way. The overall picture that emerged from research in this area shows that the phylogenetic isolation of parasitic protozoa is reflected by atypical structural and functional properties of many of their protein kinase homologues. Likewise, evidence is emerging, which suggests that the organisation of some otherwise well-conserved signal transduction pathways is divergent in some parasitic species. The differences between protein kinases of a parasite and their homologues in its host cell suggest that specific inhibition of the former can be achieved. The development of anti-parasitic drugs based on protein kinase inhibition is being pursued following two avenues: one consists of screening chemical libraries on recombinant enzymes; several protein kinases from parasitic protozoa are now available for this approach. The second approach relies on the identification of the molecular targets of kinase inhibitors which display anti-parasitic properties. This has led to promising developments in a few instances, in particular regarding PKG as a drug target against Eimeria and Toxoplasma, and purvalanol B, a purine-based CDK inhibitor which appears to affect unexpected targets in several protozoan parasites. The recent resolution of the structure of a Plasniodium protein kinase complexed with small inhibitory molecules opens the way to a rational approach towards the design of anti-parasitic drugs based on kinase inhibition. (C) 2003 Elsevier B.V. All rights reserved.