Leishmanicidal metabolites from Cochliobolus sp., an endophytic fungus isolated from Piptadenia adiantoides (Fabaceae).
Leishmanicidal metabolites from Cochliobolus sp., an endophytic fungus isolated from Piptadenia adiantoides (Fabaceae).
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DOI：
10.1371/journal.pntd.0000348
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发表时间：
2008
影响因子：
3.8
通讯作者：
Zani CL
中科院分区：
文献类型：
--
作者：
Campos FF;Rosa LH;Cota BB;Caligiorne RB;Rabello AL;Alves TM;Rosa CA;Zani CL
属于利什曼原虫和锥虫属的原生动物寄生虫是严重被忽视的热带病（NTDs）的病原，在世界上许多热带和亚热带地区国家造成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过程中，我们发现内生真菌Cochliobolus sp. （UFMGCB-555）的粗提取物在20µg mL−1的浓度下，可以杀死90%的亚马逊利什曼原虫（Leishmania amazonensis）的无梭菌样形式，并且在trypanothione reductase （TryR）试验中被100%的Ellman试剂还原抑制。UFMGCB-555是从豆科植物Piptadenia adiantoides J.F. Macbr （Fabaceae）中分离得到的，通过其核糖体DNA内部转录间隔区（ITS）序列进行鉴定。在TryR法的指导下对提取物进行色谱分离，分离出耳蜗醌A和异耳蜗醌A。这两种化合物对亚马逊松毛虫都有活性，EC50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 ~ 1.9µM）和4.1µM（95%置信区间= 3.6 ~ 4.7µM）。这些化合物对三种人类癌细胞系（MCF-7、TK-10和UACC-62）无活性，表明它们对寄生虫有一定的选择性。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一种重要化合物来源的作用，这些化合物有可能进入抗被忽视热带病药物开发的管道。属于利什曼原虫和锥虫属的原生动物是单细胞生物，可感染人类并引起毁容病变和使人衰弱或致命疾病，在世界许多热带和亚热带地区造成巨大的社会和经济影响。目前可用于治疗不同形式的利什曼病和锥虫病的药物是几十年前引进的，具有重大缺陷，特别是在疗效、治疗时间、给药途径、毒性和成本方面。在我们筛选具有利什曼原虫活性的新天然产物的过程中，我们发现生活在植物Piptadenia adiantoides中的一种真菌的粗提取物可以杀死90%的亚马逊利什曼原虫的无尾线虫样形式。在生物测定法指导下，提取液分离出耳蜗醌A和异耳蜗醌A， EC50值（杀死50%寄生虫所需的有效浓度）分别为1.7µM和4.1µM。这些化合物对三种人类癌细胞系（MCF-7/乳腺、TK-10/肾脏和UACC-62/黑色素瘤）无活性，表明对寄生虫有一定的选择性。我们的研究结果表明，耳蜗醌类可以作为开发治疗利什曼病新药的起点，并加强内生真菌作为具有相关生物活性的天然产物的重要来源的作用。
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 µg 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 EC50 values (effective concentrations required to kill 50% of the parasite) of 1.7 µM (95% confidence interval = 1.6 to 1.9 µM) and 4.1 µM (95% confidence interval = 3.6 to 4.7 µM), 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. Protozoans belonging to genera Leishmania and Trypanosoma are single-cell organisms that can infect humans and cause disfiguring lesions and debilitating or fatal diseases, with enormous social and economic impact in many tropical and sub-tropical areas of the world. The drugs currently available to treat the different forms of leishmaniasis and trypanosomiasis were introduced many decades ago and have significant drawbacks, especially in terms of efficacy, length of treatment, route of administration, toxicity, and cost. In our screening program for new natural products with leishmanicidal activity, we found that the crude extract of a fungus living within the plant Piptadenia adiantoides could kill 90% of the amastigote-like forms of Leishmania amazonensis. The bioassay-guided fractionation of the extract resulted in the isolation of cochlioquinone A and isocochlioquinone A, which showed EC50 values (effective concentrations required to kill 50% of the parasite) of 1.7 µM and 4.1 µM, respectively. These compounds were not active against three human cancer cell lines (MCF-7/mammary, TK-10/renal, and UACC-62/melanoma), indicating some degree of selectivity towards the parasites. Our results suggest that cochlioquinones may serve as starting points for developing new drugs to treat leishmaniasis and reinforce the role of endophytic fungi as an important source of natural products with relevant biological activities.
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DOI：
10.1093/jnci/83.11.757
发表时间：
1991-06-05
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
MONKS, A;SCUDIERO, D;BOYD, M
通讯作者：
BOYD, M
影响因子：
3.5
作者：
Jung, HJ;Lee, HB;Kwon, HJ
通讯作者：
Kwon, HJ
影响因子：
13.7
作者：
MASKIN, SL;FETCHICK, RJ;RINALDI, MG
通讯作者：
RINALDI, MG
影响因子：
3.3
作者：
MACHIDA, T;HIGASHI, K;OGAWARA, H
通讯作者：
OGAWARA, H
影响因子：
5.1
作者：
Osterhage, C;König, GM;Wright, AD
通讯作者：
Wright, AD