Jeffers Victoria, Yang Chunlin, Huang Sherri, Sullivan William J
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, USA
Microbiol Mol Biol Rev. 2017 Jan 11;81(1). doi: 10.1128/MMBR.00047-16. Print 2017 Mar.
Parasitic infections remain one of the most pressing global health concerns of our day, affecting billions of people and producing unsustainable economic burdens. The rise of drug-resistant parasites has created an urgent need to study their biology in hopes of uncovering new potential drug targets. It has been established that disrupting gene expression by interfering with lysine acetylation is detrimental to survival of apicomplexan (Toxoplasma gondii and Plasmodium spp.) and kinetoplastid (Leishmania spp. and Trypanosoma spp.) parasites. As "readers" of lysine acetylation, bromodomain proteins have emerged as key gene expression regulators and a promising new class of drug target. Here we review recent studies that demonstrate the essential roles played by bromodomain-containing proteins in parasite viability, invasion, and stage switching and present work showing the efficacy of bromodomain inhibitors as novel antiparasitic agents. In addition, we performed a phylogenetic analysis of bromodomain proteins in representative pathogens, some of which possess unique features that may be specific to parasite processes and useful in future drug development.
寄生虫感染仍然是当今全球最紧迫的健康问题之一，影响着数十亿人，并造成了难以承受的经济负担。耐药寄生虫的出现迫切需要对其生物学进行研究，以期发现新的潜在药物靶点。已经证实，通过干扰赖氨酸乙酰化来破坏基因表达对顶复门（弓形虫和疟原虫属）和动基体（利什曼原虫属和锥虫属）寄生虫的生存是有害的。作为赖氨酸乙酰化的“读取器”，含溴结构域蛋白已成为关键的基因表达调节因子和一类有前景的新型药物靶点。在此，我们综述了近期的研究，这些研究证明了含溴结构域蛋白在寄生虫生存能力、侵袭和阶段转换中所起的重要作用，并展示了溴结构域抑制剂作为新型抗寄生虫药物的有效性。此外，我们对代表性病原体中的含溴结构域蛋白进行了系统发育分析，其中一些具有可能特定于寄生虫过程的独特特征，对未来药物开发有用。
