Screening the Medicines for Malaria Venture Pathogen Box against piroplasm parasites
Screening the Medicines for Malaria Venture Pathogen Box against piroplasm parasites
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DOI：
10.1016/j.ijpddr.2019.06.004
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发表时间：
2019-08-01
影响因子：
4
通讯作者：
Igarashi, Ikuo
中科院分区：
文献类型：
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作者：
Nugraha, Arifin Budiman;Tuvshintulga, Bumduuren;Igarashi, Ikuo
醋氨酰地咪嗪（DA）和二丙酸咪胺威是家畜常用的抗疟药。然而，毒副作用在用这两种药物治疗的动物中很常见。因此，评价对梨形虫寄生虫具有高功效且对宿主动物具有低毒性的新型治疗剂是至关重要的。在这项研究中，由疟疾药物风险基金会提供的病原体盒中的400种化合物针对牛巴伯虫、二联巴伯虫、卡巴利巴伯虫和马泰勒虫进行了筛选。使用SYBR绿色1染色的基于荧光的方法用于初始体外筛选和半最大抑制浓度（IC 50）的测定。使用1 μ M浓度作为基线进行的初始体外筛选揭示了针对四种测试寄生虫的九种有效化合物。选择了两种“命中”化合物，即MMV 021057和MMV 675968，其显示出IC 50 < 0.3 μ M和选择性指数（SI）> 100。MMV 021057和MMV 675968对B的IC 50。bovis，牛湾（B. bigemina，T. equi和B. caballi的浓度分别为23、39、229和146 nM，以及2.9、3、25.7和2.9 nM。此外，MMV 021057和DA的组合对四种测试的寄生虫显示出相加或协同作用，而MMV 021057与MMV 675968和MMV 675968与DA的组合显示出拮抗作用。在小鼠中，与第8天未给药组相比，50 mg/kg MMV 021057和25 mg/kg MMV 675968给药组分别抑制了54%和64%的田鼠巴氏杆菌生长。有趣的是，6.25 mg/kg DA和25 mg/kg MMV 021057联合给药抑制了B。50 mg/kg MMV 021057和25 mg/kg DA单独处理的抑制率分别为54%和83%，MMV 021057和DA单独处理的抑制率分别为91.6%和83%。MMV 021057、MMV 675968以及MMV 021057与DA联合治疗是抗梨浆病药物的发展前景。
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 mu M concentration as baseline revealed nine effective compounds against four tested parasites. Two "hit" compounds, namely MMV021057 and MMV675968, that showed IC50 < 0.3 mu M 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.