Venom alkaloids against Chagas disease parasite: search for effective therapies.
Venom alkaloids against Chagas disease parasite: search for effective therapies.
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针对恰加斯病寄生虫的毒液生物碱：寻找有效的疗法。
DOI：
10.1038/s41598-020-67324-8
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发表时间：
2020
影响因子：
4.6
通讯作者：
deAl
中科院分区：
文献类型：
--
作者：
Silva,RafaelCMCosta;Fox,EduardoGP;Gomes,FabioM;Feijó,DanielF;Ramos,Isabela;Koeller,CarolinaM;Costa,TatianaFR;Rodrigues,NathaliaS;Lima,AnaP;Atella,GeorgiaC;Miranda,Kildare;Schoijet,AlejandraC;Alonso,GuillermoD;deAl
查加斯病是一种影响新世界数百万患者的重要疾病，由一种由吸血吻虫传播的原生动物引起。它可以在早期急性期用药物治疗;然而，尚未发现和开发针对慢性形式的恰加斯病的有效疗法。本文测定了从两种火蚁中提取的solenopsin生物碱对南美锥虫病病原体克氏锥虫的活性。尽管IC 50测定表明，solenopsins对寄生虫的毒性比苯并咪唑（用于恰加斯病治疗的首选药物）更大，但蚂蚁生物碱呈现出较低的选择性指数。作为暴露于生物碱的结果，寄生虫变得肿胀和圆形，具有肥大的收缩空泡和强烈的细胞质空泡化，可能导致渗透压;未检测到多个动质体和/或细胞核的积累。过表达磷脂酰肌醇3激酶--一种调节寄生虫的必需酶，也是哺乳动物细胞中solenopsin的已知靶点--并不能阻止肿胀和空泡化，也不能抵消生物碱对寄生虫的毒性作用。另外的实验结果表明，solenopsins诱导的自噬和程序性细胞死亡的克氏锥虫的类型。Solenopsins还能抑制T.在感染巨噬细胞中以浓度依赖性方式存在克氏鞭毛体，并表现出对另一种重要的病原动质体寄生虫布氏罗得西亚锥虫血流形式的活性。结果表明，solenopsins作为新型天然药物对被忽视的动质体引起的寄生虫病的潜力。
Chagas disease is an important disease affecting millions of patients in the New World and is caused by a protozoan transmitted by haematophagous kissing bugs. It can be treated with drugs during the early acute phase; however, effective therapy against the chronic form of Chagas disease has yet to be discovered and developed. We herein tested the activity of solenopsin alkaloids extracted from two species of fire ants against the protozoan parasiteTrypanosoma cruzi, the aetiologic agent of Chagas disease. Although IC50determinations showed that solenopsins are more toxic to the parasite than benznidazole, the drug of choice for Chagas disease treatment, the ant alkaloids presented a lower selectivity index. As a result of exposure to the alkaloids, the parasites became swollen and rounded in shape, with hypertrophied contractile vacuoles and intense cytoplasmic vacuolization, possibly resulting in osmotic stress; no accumulation of multiple kinetoplasts and/or nuclei was detected. Overexpressing phosphatidylinositol 3-kinase—an enzyme essential for osmoregulation that is a known target of solenopsins in mammalian cells—did not prevent swelling and vacuolization, nor did it counteract the toxic effects of alkaloids on the parasites. Additional experimental results suggested that solenopsins induced a type of autophagic and programmed cell death inT. cruzi. Solenopsins also reduced the intracellular proliferation ofT. cruziamastigotes in infected macrophages in a concentration-dependent manner and demonstrated activity againstTrypanosoma brucei rhodesiensebloodstream forms, which is another important aetiological kinetoplastid parasite. The results suggest the potential of solenopsins as novel natural drugs against neglected parasitic diseases caused by kinetoplastids.