疟疾风险投资病原体盒筛选抗梨形虫寄生虫。
Screening the Medicines for Malaria Venture Pathogen Box against piroplasm parasites.
机构信息
National Research Center for Protozoan Diseases, Obihiro University of Agriculture Veterinary Medicine, Nishi 2 Sen-13, Inada-cho, Obihiro, Hokkaido, 080-8555, Japan; Department of Animal Infectious Diseases and Veterinary Public Health, Faculty of Veterinary Medicine, IPB University, Jl. Agatis, Kampus IPB Dramaga, Bogor, Jawa Barat, 16680, Indonesia.
National Research Center for Protozoan Diseases, Obihiro University of Agriculture Veterinary Medicine, Nishi 2 Sen-13, Inada-cho, Obihiro, Hokkaido, 080-8555, Japan.
出版信息
Int J Parasitol Drugs Drug Resist. 2019 Aug;10:84-90. doi: 10.1016/j.ijpddr.2019.06.004. Epub 2019 Jun 19.
Diminazene aceturate (DA) and imidocarb dipropionate are commonly used in livestock as antipiroplasm agents. However, toxic side effects are common in animals treated with these two drugs. Therefore, evaluations of novel therapeutic agents with high efficacy against piroplasm parasites and low toxicity to host animals are of paramount importance. In this study, the 400 compounds in the Pathogen Box provided by the Medicines for Malaria Venture foundation were screened against Babesia bovis, Babesia bigemina, Babesia caballi, and Theileria equi. A fluorescence-based method using SYBR Green 1 stain was used for initial in vitro screening and determination of the half maximal inhibitory concentration (IC50). The initial in vitro screening performed using a 1 μM concentration as baseline revealed nine effective compounds against four tested parasites. Two "hit" compounds, namely MMV021057 and MMV675968, that showed IC50 < 0.3 μM and a selectivity index (SI)> 100 were selected. The IC50s of MMV021057 and MMV675968 against B. bovis, B. bigemina, T. equi and B. caballi were 23, 39, 229, and 146 nM, and 2.9, 3, 25.7, and 2.9 nM, respectively. In addition, a combination of MMV021057 and DA showed additive or synergistic effects against four tested parasites, while combinations of MMV021057 with MMV675968 and of MMV675968 with DA showed antagonistic effects. In mice, treated with 50 mg/kg MMV021057 and 25 mg/kg MMV675968 inhibited the growth of Babesia microti by 54 and 64%, respectively, as compared to the untreated group on day 8. Interestingly, a combination treatment with 6.25 mg/kg DA and 25 mg/kg MMV021057 inhibited B. microti by 91.6%, which was a stronger inhibition than that by single treatments with 50 mg/kg MMV021057 and 25 mg/kg DA, which showed 54 and 83% inhibition, respectively. Our findings indicated that MMV021057, MMV675968, and the combination treatment with MMV021057 and DA are prospects for further development of antipiroplasm drugs.
二脒那嗪乙酰替（DA）和二硝咪唑丙酸盐通常作为抗梨形虫药物用于牲畜。然而，这两种药物治疗的动物常出现毒性副作用。因此，评估对梨形虫寄生虫具有高效力和对宿主动物低毒性的新型治疗剂至关重要。在这项研究中，从疟疾药物发现基金会的病原体盒中筛选了 400 种化合物，以对抗牛巴贝斯虫、双芽巴贝斯虫、马巴贝斯虫和马媾疫锥虫。使用 SYBR Green 1 染色的荧光法用于初始体外筛选和测定半最大抑制浓度（IC50）。使用 1 μM 浓度作为基线进行的初始体外筛选显示，有 9 种有效化合物对 4 种测试寄生虫具有活性。两种“命中”化合物 MMV021057 和 MMV675968 的 IC50<0.3 μM 和选择性指数（SI）>100，被选中。MMV021057 和 MMV675968 对牛巴贝斯虫、双芽巴贝斯虫、马媾疫锥虫和马巴贝斯虫的 IC50 分别为 23、39、229 和 146 nM 和 2.9、3、25.7 和 2.9 nM。此外，MMV021057 和 DA 的组合对 4 种测试寄生虫表现出相加或协同作用，而 MMV021057 与 MMV675968 的组合和 MMV675968 与 DA 的组合则表现出拮抗作用。在 50mg/kg MMV021057 和 25mg/kg MMV675968 处理的小鼠中，与未处理组相比，第 8 天巴贝斯微孢子虫的生长分别抑制了 54%和 64%。有趣的是，6.25mg/kg DA 和 25mg/kg MMV021057 的联合治疗对巴贝斯微孢子虫的抑制率为 91.6%，比单独使用 50mg/kg MMV021057 和 25mg/kg DA 时的抑制率（分别为 54%和 83%）更强。我们的研究结果表明，MMV021057、MMV675968 和 MMV021057 与 DA 的联合治疗是进一步开发抗梨形虫药物的前景。
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