利用酶性乱交来设计一个高度选择性的抗真菌和抗增殖性青素类型的专注库
Martina Werneburg1, Benjamin Busch, Jing He
1Leibniz Institute for Natural Product Research and Infection Biology, HKI, Dept. of Biomolecular Chemistry, Beutenbergstr. 11a, 07745 Jena, Germany.
Journal of the American Chemical Society
|July 29, 2010
概括
研究人员修改了天然产品黄金,以创造新的类似物. 一些类似物显示出降低的毒性和增强的抗增殖作用,四二环是抗真菌活性的关键.
科学领域:
- 自然产品化学 自然产品化学
- 合成生物学 合成生物学
- 药用化学 医学化学
背景情况:
- 奥雷是Streptomyces thioluteus的一种混合代谢物,具有独特的结构,包括一小部分尼特罗阿里尔,四基环和环.
- 其已知的抗微生物和抗瘤活动需要对其结构修改进行调查,以提高其生物活性.
研究的目的:
- 创建一个图书馆的 aureothin 类似物与修改结构.
- 评估这些修改对生物活性的影响,包括细胞毒性和抗增殖作用.
- 确定奥雷素选择性活性至关重要的结构元素.
主要方法:
- 采用了一种综合方法,结合了突变合成,生物转化和组合生物合成.
- 利用了聚基酸合成酶的散乱性和环形形成途径的可塑性.
- 在制剂规模上生产和表征了15种新型的黄氨酸类似物.
主要成果:
- 创建了15种新型黄氨酸类似物库,其中包括烯残留物,环和氧化骨干的修改.
- 与原始化合物相比,几种新的类型呈现出较低的细胞毒性.
- 观察到各种青红素衍生物的抗增殖活性有所改善.
- 确定了四基 (THF) 环对于对病原性真菌的选择性活性至关重要.
结论:
- 通过合成生物学方法对黄氨酸的结构调节产生了具有改善治疗潜力的类似物.
- 甲基酸环对于青素类似物具有选择性抗真菌活性至关重要.
- 这些发现为开发由青素衍生的新型抗微生物和抗瘤剂提供了基础.
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