Laboratório de Química de Produtos Naturais, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil.
PLoS Negl Trop Dis. 2008;2(12):e348. doi: 10.1371/journal.pntd.0000348. Epub 2008 Dec 16.
Protozoan parasites belonging to genera Leishmania and Trypanosoma are the etiological agents of severe neglected tropical diseases (NTDs) that cause enormous social and economic impact in many countries of tropical and sub-tropical areas of the world. In our screening program for new drug leads from natural sources, we found that the crude extract of the endophytic fungus Cochliobolus sp. (UFMGCB-555) could kill 90% of the amastigote-like forms of Leishmania amazonensis and inhibit by 100% Ellman's reagent reduction in the trypanothione reductase (TryR) assay, when tested at 20 microg mL(-1). UFMGCB-555 was isolated from the plant Piptadenia adiantoides J.F. Macbr (Fabaceae) and identified based on the sequence of the internally transcribed spacer (ITS) regions of its ribosomal DNA. The chromatographic fractionation of the extract was guided by the TryR assay and resulted in the isolation of cochlioquinone A and isocochlioquinone A. Both compounds were active in the assay with L. amazonensis, disclosing EC(50) values (effective concentrations required to kill 50% of the parasite) of 1.7 microM (95% confidence interval = 1.6 to 1.9 microM) and 4.1 microM (95% confidence interval = 3.6 to 4.7 microM), respectively. These compounds were not active against three human cancer cell lines (MCF-7, TK-10, and UACC-62), indicating some degree of selectivity towards the parasites. These results suggest that cochlioquinones are attractive lead compounds that deserve further investigation aiming at developing new drugs to treat leishmaniasis. The findings also reinforce the role of endophytic fungi as an important source of compounds with potential to enter the pipeline for drug development against NTDs.
原生动物寄生虫属于利什曼原虫属和锥虫属，是严重被忽视的热带病（NTDs）的病原体，在世界上许多热带和亚热带国家造成了巨大的社会和经济影响。在我们从天然来源筛选新药先导物的计划中，我们发现内生真菌 Cochliobolus sp.（UFMGCB-555）的粗提取物能够杀死 90%的美洲利什曼原虫类似无鞭毛体形式，并在 20μg mL(-1)时在 Trypanothione 还原酶（TryR）测定中完全抑制 Ellman 试剂还原。UFMGCB-555 是从植物 Piptadenia adiantoides J.F. Macbr（豆科）中分离出来的，并根据其核糖体 DNA 的内部转录间隔区（ITS）序列进行鉴定。提取物的色谱分离是根据 TryR 测定进行的，结果分离出 Cochlioquinone A 和 Isocochlioquinone A。这两种化合物在针对 L. amazonensis 的测定中均具有活性，显示出 EC(50)值（杀死 50%寄生虫所需的有效浓度）分别为 1.7μM（95%置信区间 = 1.6 至 1.9μM）和 4.1μM（95%置信区间 = 3.6 至 4.7μM）。这些化合物对三种人类癌细胞系（MCF-7、TK-10 和 UACC-62）没有活性，表明它们对寄生虫具有一定程度的选择性。这些结果表明 Cochlioquinones 是有吸引力的先导化合物，值得进一步研究，旨在开发治疗利什曼病的新药。这些发现还加强了内生真菌作为具有潜在进入 NTDs 药物开发管道的化合物的重要来源的作用。
