Department of Infectious Diseases and Pathobiology, Institute of Parasitology, Vetsuisse Faculty, University of Bern, Länggass-Strasse 122, 3012 Bern, Switzerland.
Graduate School for Cellular and Biomedical Sciences, University of Bern, Mittelstrasse 43, 3012 Bern, Switzerland.
Molecules. 2020 Mar 24;25(6):1460. doi: 10.3390/molecules25061460.
(1) Background: is a major cause of abortion in cattle and represents a veterinary health problem of great economic significance. In order to identify novel chemotherapeutic agents for the treatment of neosporosis, the Medicines for Malaria Venture (MMV) Malaria Box, a unique collection of anti-malarial compounds, were screened against tachyzoites, and the most efficient compounds were characterized in more detail. (2) Methods: A beta-galactosidase reporter strain grown in human foreskin fibroblasts was treated with 390 compounds from the MMV Malaria Box. The ICs of nine compounds were determined, all of which had been previously been shown to be active against another apicomplexan parasite, . The effects of three of these compounds on the ultrastructure of tachyzoites were further investigated by transmission electron microscopy at different timepoints after initiation of drug treatment. (3) Results: Five MMV Malaria Box compounds exhibited promising ICs below 0.2 µM. The compound with the lowest IC, namely 25 nM, was MMV665941. This compound and two others, MMV665807 and MMV009085, specifically induced distinct alterations in the tachyzoites. More specifically, aberrant structural changes were first observed in the parasite mitochondrion, and subsequently progressed to other cytoplasmic compartments of the tachyzoites. The pharmacokinetic (PK) data obtained in mice suggest that treatment with MMV665941 could be potentially useful for further in vivo studies. (4) Conclusions: We have identified five novel compounds with promising activities against , the effects of three of these compounds were studies by transmission electron microscopy (TEM). Their modes of action are unknown and require further investigation.
（1）背景：是牛流产的主要原因，也是兽医健康的重大经济问题。为了寻找治疗新孢子虫病的新型化学治疗药物，疟疾药物 Venture（MMV）疟疾药箱筛选了抗疟化合物，对速殖子进行了筛选，对最有效的化合物进行了更详细的特征描述。（2）方法：在人包皮成纤维细胞中生长的β-半乳糖苷酶报告株用 MMV 疟疾药箱中的 390 种化合物进行处理。测定了 9 种化合物的 IC，这些化合物之前已被证明对另一种顶复门寄生虫有效。用透射电子显微镜进一步研究了其中 3 种化合物对速殖子超微结构的影响，在开始药物治疗后不同时间点观察。（3）结果：有 5 种 MMV 疟疾药箱化合物表现出有希望的 IC 低于 0.2 μM。IC 最低的化合物是 MMV665941，为 25 nM。这种化合物和另外两种化合物，MMV665807 和 MMV009085，专门诱导速殖子发生明显改变。更具体地说，首先观察到寄生虫线粒体出现异常结构变化，随后速殖子的其他细胞质隔室也出现了这种变化。在小鼠中获得的药代动力学（PK）数据表明，用 MMV665941 治疗可能对进一步的体内研究有用。（4）结论：我们已经确定了 5 种对有潜在活性的新型化合物，其中 3 种化合物的作用机制尚不清楚，需要进一步研究。
