Biomedicine Discovery Institute, Department of Microbiology, Monash University Clayton, Melbourne, VIC 3800, Australia.
Department of Chemical Biology and Bioimaging, Wroclaw University of Science and Technology, Wyb. Wyspianskiego 27, 50-370 Wroclaw, Poland.
Biochem J. 2020 Oct 16;477(19):3819-3832. doi: 10.1042/BCJ20200569.
Toxoplasmosis is a parasitic disease caused by infection with Toxoplasma gondii that currently has few therapeutic options. The M1 aminopeptidase enzymes have been shown to be attractive targets for anti-parasitic agents and/or vaccine candidates, suggesting potential to re-purpose inhibitors between parasite M1 aminopeptidase targets. The M1 aminopeptidase TgAPN2 has been suggested to be a potential new drug target for toxoplasmosis. Here we investigate the structure and function of TgAPN2, a homologue of the antimalarial drug target PfA-M1, and evaluate the capacity to use inhibitors that target PfA-M1 against TgAPN2. The results show that despite a similar overall fold, the TgAPN2 has a unique substrate specificity and inhibition profile. Sequence and structure differences are investigated and show how comparative structure-activity relationships may provide a route to obtaining potent inhibitors of TgAPN2.
弓形虫病是一种由刚地弓形虫感染引起的寄生虫病，目前治疗方法有限。M1 氨肽酶酶已被证明是抗寄生虫药物和/或疫苗候选物的有吸引力的靶标，这表明有潜力在寄生虫 M1 氨肽酶靶标之间重新利用抑制剂。M1 氨肽酶 TgAPN2 被认为是弓形虫病的一个有潜力的新药物靶点。在这里，我们研究了 TgAPN2 的结构和功能，TgAPN2 是抗疟药物靶标 PfA-M1 的同源物，并评估了使用针对 PfA-M1 的抑制剂来靶向 TgAPN2 的能力。结果表明，尽管具有相似的整体折叠，但 TgAPN2 具有独特的底物特异性和抑制谱。研究了序列和结构差异，并展示了如何通过比较结构-活性关系来获得 TgAPN2 的有效抑制剂。
