Kamyingkird Ketsarin, Cao Shinuo, Tuvshintulga Bumduuren, Salama Akram, Mousa Ahmed Abdelmoniem, Efstratiou Artemis, Nishikawa Yoshifumi, Yokoyama Naoaki, Igarashi Ikuo, Xuan Xuenan
National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, 080-8555, Japan; Department of Parasitology, Faculty of Veterinary Medicine, Kasetsart University, Bangkok, 10900, Thailand.
Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Nangang District, Harbin, 150001, China.
Exp Parasitol. 2017 May;176:59-65. doi: 10.1016/j.exppara.2017.03.002. Epub 2017 Mar 9.
Theileria equi and Babesia caballi are the causative agents of equine piroplasmosis (EP), which affects equine production in various parts of the world. However, a safe and effective drug is not currently available for treatment of EP. Dihydroorotate dehydrogenase (DHODH) is the fourth enzyme in the de novo pyrimidine synthesis pathway and has been known as a novel drug target for several apicomplexan protozoan parasites. In this study, we evaluated four DHODH inhibitors; atovaquone (ATV), leflunomide (LFN), brequinar (Breq), and 7-hydroxy-5-[1,2,4] triazolo [1,5,a] pyrimidine (TAZ) on the growth of T. equi and B. caballi in vitro and compared them to diminacene aceturate (Di) as the control drug. The growth of T. equi and B. caballi was significantly hindered by all inhibitors except TAZ. The half maximal inhibitory concentration (IC) of ATV, LFN, Breq and Di against T. equi was approximately 0.028, 109, 11 and 40 μM, respectively, whereas the IC of ATV, LFN, Breq and Di against B. caballi was approximately 0.128, 193, 5.2 and 16.2 μM, respectively. Using bioinformatics and Western blot analysis, we showed that TeDHODH was similar to other Babesia parasite DHODHs, and confirmed that targeting DHODHs could be useful for the development of novel chemotherapeutics for treatment of EP.
马泰勒虫和驽巴贝斯虫是马焦虫病（EP）的病原体，该病影响着世界各地区的养马业。然而，目前尚无安全有效的药物可用于治疗EP。二氢乳清酸脱氢酶（DHODH）是从头嘧啶合成途径中的第四个酶，并且已成为几种顶复门原生动物寄生虫的新型药物靶点。在本研究中，我们评估了四种DHODH抑制剂；阿托伐醌（ATV）、来氟米特（LFN）、布喹那（Breq）和7-羟基-5-[1,2,4]三唑并[1,5,a]嘧啶（TAZ）对体外培养的马泰勒虫和驽巴贝斯虫生长的影响，并将它们与作为对照药物的乙酰氨基阿维菌素（Di）进行比较。除TAZ外，所有抑制剂均显著抑制了马泰勒虫和驽巴贝斯虫的生长。ATV、LFN、Breq和Di对马泰勒虫的半数最大抑制浓度（IC）分别约为0.028、109、11和40 μM，而ATV、LFN、Breq和Di对驽巴贝斯虫的IC分别约为0.128、193、5.2和16.2 μM。通过生物信息学和蛋白质免疫印迹分析，我们表明马泰勒虫DHODH与其他巴贝斯属寄生虫的DHODH相似，并证实靶向DHODH可能有助于开发用于治疗EP的新型化学治疗药物。
