Department of Biological Sciences, Clemson University, Clemson, SC 29634, United States; Eukaryotic Pathogens Innovation Center, Clemson University, Clemson, SC 29634, United States.
Department of Biological Sciences, Clemson University, Clemson, SC 29634, United States; Eukaryotic Pathogens Innovation Center, Clemson University, Clemson, SC 29634, United States.
Int J Parasitol. 2021 Jul;51(8):599-611. doi: 10.1016/j.ijpara.2020.12.007. Epub 2021 Mar 13.
Protozoan parasites are single-celled eukaryotic organisms that cause significant human disease and pose a substantial health and socioeconomic burden worldwide. They are responsible for at least 1 million deaths annually. The treatment of such diseases is hindered by the ability of parasites to form latent cysts, develop drug resistance, or be transmitted by insect vectors. Additionally, these pathogens have developed complex mechanisms to alter host gene expression. The prevalence of these diseases is predicted to increase as climate change leads to the augmentation of ambient temperatures, insect ranges, and warm water reservoirs. Therefore, the discovery of novel treatments is necessary. Transcription factors lie at the junction of multiple signalling pathways in eukaryotes and aberrant transcription factor function contributes to the progression of numerous human diseases including cancer, diabetes, inflammatory disorders and cardiovascular disease. Transcription factors were previously thought to be undruggable. However, due to recent advances, transcription factors now represent appealing drug targets. It is conceivable that transcription factors, and the pathways they regulate, may also serve as targets for anti-parasitic drug design. Here, we review transcription factors and transcriptional modulators of protozoan parasites, and discuss how they may be useful in drug discovery. We also provide information on transcription factors that play a role in stage conversion of parasites, TATA box-binding proteins, and transcription factors and cofactors that participate with RNA polymerases I, II and III. We also highlight a significant gap in knowledge in that the transcription factors of some of parasites have been under-investigated. Understanding parasite transcriptional pathways and how parasites alter host gene expression will be essential in discovering innovative drug targets.
原生动物寄生虫是单细胞真核生物，会导致严重的人类疾病，并在全球范围内造成重大的健康和社会经济负担。它们每年至少导致 100 万人死亡。寄生虫形成潜伏囊肿、产生耐药性或通过昆虫媒介传播的能力阻碍了这些疾病的治疗。此外，这些病原体已经发展出复杂的机制来改变宿主基因表达。随着气候变化导致环境温度、昆虫范围和温水储层的增加，这些疾病的流行率预计将会增加。因此，有必要发现新的治疗方法。转录因子位于真核生物中多个信号通路的交汇点，异常转录因子功能会导致多种人类疾病的进展，包括癌症、糖尿病、炎症性疾病和心血管疾病。转录因子以前被认为是不可成药的。然而，由于最近的进展，转录因子现在成为有吸引力的药物靶点。可以想象，转录因子及其调节的途径也可能成为抗寄生虫药物设计的靶点。在这里，我们回顾了原生动物寄生虫的转录因子和转录调节剂，并讨论了它们在药物发现中的应用。我们还提供了有关在寄生虫阶段转换中起作用的转录因子、TATA 盒结合蛋白以及与 RNA 聚合酶 I、II 和 III 一起参与的转录因子和辅助因子的信息。我们还强调了一个重要的知识差距，即一些寄生虫的转录因子尚未得到充分研究。了解寄生虫的转录途径以及寄生虫如何改变宿主基因表达将是发现创新药物靶点的关键。
