Cota Betania Barros, Rosa Luiz Henrique, Caligiorne Rachel Basques, Rabello Ana Lúcia Teles, Almeida Alves Tânia Maria, Rosa Carlos Augusto, Zani Carlos Leomar
Laboratório de Química de Produtos Naturais, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Brazil.
FEMS Microbiol Lett. 2008 Aug;285(2):177-82. doi: 10.1111/j.1574-6968.2008.01221.x. Epub 2008 Jun 28.
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 microg mL(-1). Fractionation of the extract identified altenusin, a biphenyl derivative with an IC50 value of 4.3+/-0.3 microM 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.
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多种疾病的病原体，迫切需要有效且价格合理的治疗方法。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，以寻找可作为开发针对这些疾病药物先导的天然产物。锥虫硫醇还原酶（TR）是一种参与保护锥虫属和利什曼原虫属免受氧化应激的酶，被认为是一个经过验证的药物靶点。内生真菌链格孢菌（UFMGCB55）是从植物三翅六棱菊（菊科）中分离出来的，已知该植物含有杀锥虫化合物。链格孢菌培养物的有机提取物在20微克/毫升的浓度下进行测试时，能够抑制TR达99%。对提取物进行分离鉴定出了altenusin，一种联苯衍生物，在TR测定中的IC50值为4.3±0.3微摩尔。该化合物是其同类中首个显示出TR抑制活性的，为设计更有效的衍生物开辟了新的前景，这些衍生物可作为治疗锥虫病和利什曼病的新型化疗药物的先导。
