Novel synthetic compounds with endoperoxide structure damage juvenile stage of Schistosoma mansoni by targeting lysosome-like organelles
Novel synthetic compounds with endoperoxide structure damage juvenile stage of Schistosoma mansoni by targeting lysosome-like organelles
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具有内过氧化物结构的新型合成化合物通过靶向溶酶体样细胞器损害曼氏血吸虫的幼年期
DOI：
10.1016/j.parint.2016.10.013
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发表时间：
2017
期刊：
影响因子：
1.9
通讯作者：
Ohta N.
中科院分区：
文献类型：
--
作者：
Yamabe M;Kumagai T;Shimogawara R;Blay EA;Hino A;Ichimura K;Sato A;Kim HS;Ohta N.
新合成的化合物1，2，6，7-四氧杂螺[7.11]十九烷（N-89）是一种新的抗疟疾药物候选物，也是一种很有前途的抗血吸虫药物候选物，对曼氏血吸虫童虫有杀灭作用。为了研究N-89如何杀死染色体，我们使用了N-89的衍生物，6-（1，2，6，7-四氧杂螺[7.11]十九碳-4-基）己-1-醇（N-251），这使得我们能够与荧光试剂缀合。首先，N-251对曼氏血吸虫幼虫有较强的体外杀灭作用。超微结构观察显示，N-251处理组虫体内溶酶体样细胞器或髋臼腺破坏，胞质溶解。对于罗丹明结合的N-251和细胞器标记物，我们观察到N-251在酸性细胞器中积累。此外，N-251给药组中这些酸性细胞器中的LysoTracker信号随时间消失。最后，我们观察到N-251处理组的溶酶体特异性酶组织蛋白酶B的活性也随着酸性细胞器标记信号的改变而降低。这些结果表明，我们合成的化合物诱导功能障碍或破坏酸性溶酶体样细胞器，最终导致蠕虫死亡。
The new synthetic compound 1,2,6,7-tetraoxaspiro[7.11]nonadecan (N-89), a novel anti-malaria drug candidate, is also a promising drug candidate against schistosomiasis with killing effects against juvenile stage ofS.mansoni. In order to investigate how N-89 kills schistosomes, we used a derivative of N-89, 6-(1,2,6,7-tetraoxaspiro[7.11] nonadec-4-yl)hexan-1-ol (N-251), which enables us to conjugate with fluorescent reagents. Firstly, N-251 showed strong killing effects to larvae ofS.mansoni in vitro. Ultrastructural analysis showed the disruptions of the lysosome-like organelles or the acetabular glands, followed by cytoplasmic lysis inside the worm body in N-251-treated group under electron microscopy. For rhodamine-conjugated N-251 and organelle markers, we observed that N-251 accumulated in acidic organelle. In addition, LysoTracker signals in these acidic organelles disappeared in N-251-treated group over time. Finally, we observed that the activity of cathepsin B, a lysosome-specific enzyme, was also decreased together with alternation of acidic organelle marker signal by N-251-treated group. These results suggested that our synthesized compounds induced the dysfunction or the disruption of acidic lysosome-like organelles and finally led to worm death.