Doerig Christian
Wellcome Centre for Molecular Parasitology, University of Glasgow, INSERM, 56 Dumbarton Road, Glasgow G11 6NU, Scotland, UK.
Biochim Biophys Acta. 2004 Mar 11;1697(1-2):155-68. doi: 10.1016/j.bbapap.2003.11.021.
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 Plasmodium 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 Plasmodium 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.
感染人类的寄生原生动物对公共卫生有着惊人的影响，尤其是在发展中世界。此外，几种原生动物物种是家畜的主要病原体，对粮食生产有相当大的影响。在许多情况下，寄生虫已经对现有的化疗药物产生了抗性，因此寻找替代药物成为当务之急。鉴于目前对蛋白激酶抑制剂作为针对多种疾病的潜在药物的兴趣，人们正在探索蛋白激酶可能成为新型抗寄生虫药物靶点的可能性。对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），还有几个正在进行中。该领域研究得出的总体情况表明，寄生原生动物的系统发育隔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在某些寄生物种中的组织方式存在差异。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正沿着两条途径进行：一条是在重组酶上筛选化学文库；现在有几种来自寄生原生动物的蛋白激酶可用于这种方法。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点。在一些情况下，这已经带来了有希望的进展，特别是将PKG作为针对艾美球虫和弓形虫的药物靶点，以及嘌呤基CDK抑制剂嘌呤醇B，它似乎在几种原生动物寄生虫中影响意想不到的靶点。最近疟原虫蛋白激酶与小抑制分子复合的结构解析为基于激酶抑制的抗寄生虫药物设计开辟了一条合理的途径。
