Institute of Parasitology, Vetsuisse Faculty, University of Berne, Länggass-Strasse 122, CH-3012 Berne, Switzerland.
Centre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences G2, North-West University Potchefstroom Campus, 11 Hoffman Street, Potchefstroom 2531, South Africa.
Int J Antimicrob Agents. 2015 Jul;46(1):88-93. doi: 10.1016/j.ijantimicag.2015.02.020. Epub 2015 Apr 14.
From a panel of 34 artemisinin derivatives tested in vitro, artemisone, GC007 and GC012 were most efficacious at inhibiting Neospora caninum replication (IC50 values of 3-54nM), did not notably impair the invasiveness of tachyzoites and were non-toxic for human foreskin fibroblasts (HFFs). Transmission electron microscopy of drug-treated N. caninum-infected HFFs demonstrated severe alterations in the parasite cytoplasm, changes in the composition of the matrix of the parasitophorous vacuole (PV) and diminished integrity of the PV membrane. To exert parasiticidal activity, parasites had to be cultured continuously in the presence of 5μM artemisone or GC007 for 3 weeks. N. caninum tachyzoites readily adapted to a stepwise increase in concentrations (0.5-10μM) of GC012, but not to artemisone or GC007. Drugs induced the expression of elevated levels of NcBAG1 and NcSAG4 mRNA, but only NcBAG1 could be detected by immunofluorescence. Thus, artemisinin derivatives represent interesting leads that should be investigated further.
从 34 种青蒿素衍生物的小组测试来看，青蒿琥酯、GC007 和 GC012 在抑制刚地弓形虫复制方面最有效（IC50 值为 3-54nM），不会显著损害速殖子的侵袭性，对人包皮成纤维细胞（HFF）也没有毒性。药物处理的弓形虫感染的 HFF 的透射电子显微镜显示，寄生虫细胞质严重改变，寄生泡（PV）基质的组成发生变化，PV 膜的完整性降低。为了发挥杀寄生虫活性，寄生虫必须在存在 5μM 青蒿琥酯或 GC007 的情况下连续培养 3 周。刚地弓形虫速殖子很容易适应 GC012 浓度的逐步增加（0.5-10μM），但不能适应青蒿琥酯或 GC007。药物诱导 NcBAG1 和 NcSAG4 mRNA 的表达水平升高，但只有 NcBAG1 可以通过免疫荧光检测到。因此，青蒿素衍生物是很有前途的先导化合物，值得进一步研究。
