Institute of Parasitology, University of Berne, Berne, Switzerland.
Int Rev Cell Mol Biol. 2013;301:359-401. doi: 10.1016/B978-0-12-407704-1.00007-5.
Antiparasitic chemotherapy is an important issue for drug development. Traditionally, novel compounds with antiprotozoan activities have been identified by screening of compound libraries in high-throughput systems. More recently developed approaches employ target-based drug design supported by genomics and proteomics of protozoan parasites. In this chapter, the drug targets in protozoan parasites are reviewed. The gene-expression machinery has been among the first targets for antiparasitic drugs and is still under investigation as a target for novel compounds. Other targets include cytoskeletal proteins, proteins involved in intracellular signaling, membranes, and enzymes participating in intermediary metabolism. In apicomplexan parasites, the apicoplast is a suitable target for established and novel drugs. Some drugs act on multiple subcellular targets. Drugs with nitro groups generate free radicals under anaerobic growth conditions, and drugs with peroxide groups generate radicals under aerobic growth conditions, both affecting multiple cellular pathways. Mefloquine and thiazolides are presented as examples for antiprotozoan compounds with multiple (side) effects. The classic approach of drug discovery employing high-throughput physiological screenings followed by identification of drug targets has yielded the mainstream of current antiprotozoal drugs. Target-based drug design supported by genomics and proteomics of protozoan parasites has not produced any antiparasitic drug so far. The reason for this is discussed and a synthesis of both methods is proposed.
抗寄生虫化疗是药物开发的一个重要问题。传统上，通过高通量系统中的化合物库筛选来鉴定具有抗原生动物活性的新型化合物。最近开发的方法采用基于基因组学和寄生虫蛋白质组学的靶标药物设计。在本章中，综述了原生动物寄生虫的药物靶标。基因表达机制一直是抗寄生虫药物的首批靶标之一，并且仍然是新型化合物的研究目标。其他靶标包括细胞骨架蛋白、参与细胞内信号转导的蛋白质、膜和参与中间代谢的酶。在顶复门寄生虫中，质体是现有和新型药物的合适靶标。一些药物作用于多个亚细胞靶标。具有硝基的药物在厌氧生长条件下产生自由基，具有过氧化物基团的药物在需氧生长条件下产生自由基，两者都影响多个细胞途径。以氯喹和噻唑类为例，介绍了具有多种（副作用）的抗原生动物化合物。采用高通量生理筛选鉴定药物靶标作为经典的药物发现方法，产生了目前大多数抗原生动物药物。基于基因组学和寄生虫蛋白质组学的基于靶标的药物设计迄今为止尚未产生任何抗寄生虫药物。讨论了产生这种情况的原因，并提出了两种方法的综合。
