Altenusin, a biphenyl isolated from the endophytic fungus Alternaria sp., inhibits trypanothione reductase from Trypanosoma cruzi
Altenusin, a biphenyl isolated from the endophytic fungus Alternaria sp., inhibits trypanothione reductase from Trypanosoma cruzi
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DOI：
10.1111/j.1574-6968.2008.01221.x
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发表时间：
2008-08-01
影响因子：
2.1
通讯作者：
Zani, Carlos Leomar
中科院分区：
文献类型：
--
作者：
Cota, Betania Barros;Rosa, Luiz Henrique;Zani, Carlos Leomar
属于锥虫属和利什曼原虫属的寄生原生动物物种是世界热带地区几种疾病的病原体，迫切需要有效和负担得起的治疗。在这方面，我们正在筛选巴西的生物多样性，特别是其植物群和真菌群，寻找可以作为治疗这些疾病的药物开发先导的天然产品。锥虫硫酮还原酶（TR）是一种参与保护锥虫属和利什曼原虫属物种免受氧化应激的酶，被认为是一种经验证的药物靶标。从已知含有杀锥虫化合物的植物Trixis vauthieri DC（菊科）中分离内生真菌链格孢属（Alternaria sp.）（UFMGCB 55）。当在20 μ g/mL（-1）下测试时，链格孢属培养物的有机提取物能够抑制TR达99%。提取物的分级分离鉴定了Altenusin，一种联苯衍生物，在TR测定中的IC 50值为4.3 +/- 0.3 μ M。该化合物是同类中第一个显示TR抑制活性的化合物，为设计更有效的衍生物开辟了新的前景，这些衍生物可以作为治疗锥虫病和利什曼病的新化疗药物的药物先导。
Parasitic protozoan species belonging to the genera Trypanosoma and Leishmania are the etiological agents of several diseases in tropical areas of the world, for which there is an urgent need for effective and affordable treatment. In this regard, we are screening the Brazilian biodiversity, especially its flora and mycota, for natural products that could serve as leads for drug development against these diseases. Trypanothione reductase (TR) is an enzyme involved in the protection of Trypanosoma and Leishmania species against oxidative stress, and is considered to be a validated drug target. The endophytic fungus Alternaria sp. (UFMGCB55) was isolated from the plant Trixis vauthieri DC (Asteraceae), known to contain trypanocidal compounds. The organic extract of the culture of Alternaria sp. was able to inhibit TR by 99%, when tested at 20 mu g mL(-1). Fractionation of the extract identified altenusin, a biphenyl derivative with an IC50 value of 4.3 +/- 0.3 mu M in the TR assay. This compound is the first in its class to have shown TR inhibitory activity, opening new perspectives for the design of more effective derivatives that could serve as drug leads for new chemotherapeutic agents to treat trypanosomiasis and leishmaniasis.