血法林-环菲林相互作用:降解工作,合成宏环类类似物,X射线晶体结构和结合数据
Richard Sedrani1, Jörg Kallen, Luisa M Martin Cabrejas
1Transplantation Research, Novartis Pharma AG, S-507.312, CH-4002 Basel, Switzerland.
Journal of the American Chemical Society
|March 27, 2003
概括
新型免疫抑制剂桑格利弗林A强烈与环林A结合. 它的宏环部分单独调解这种高亲和力,为免疫抑制药物设计提供了洞察力.
科学领域:
- 自然产品化学 自然产品化学
- 免疫学 免疫学 免疫学
- 结构生物学 结构生物学
背景情况:
- 桑格利法林A (SFA) 是一种具有强大的免疫抑制性质的新型天然产品.
- SFA对环素A具有很高的亲和力,与环素A (CsA) 不同.
- 它独特的作用机制和复杂的结构需要进行详细的研究.
研究的目的:
- 阐明桑格利法林A与环菲林A相互作用的结构基础.
- 确定负责SFA高亲和力的关键分子成分.
- 探索用于新型免疫抑制药物开发的结构-活性关系.
主要方法:
- 选择性氧化裂变SFA以产生关键片段.
- 使用IC50测试来确定亲和力.
- 复杂的环素A与SFA类似物的X射线晶体学.
- 通过闭环转化合成的宏类同类的化学合成.
主要成果:
- SFA 的宏环部分完全负责其与环素A 的高度亲和力 (IC50 = 29 nM 对于片段 2).
- X射线结晶学显示,SFA类似物与CsA.结合于与CSA.相同的疏水口袋.
- 结构-活性关系研究确定了宏循环中的关键功能,包括二烯,多和三单元.
结论:
- 桑格利弗林A的宏环片段是环林A结合的高度优化的药.
- SFA代表了一类新的免疫抑制剂,其独特的机制是由其宏循环结构介导的.
- 这些发现为设计针对环菲林A的新免疫抑制剂提供了基础.
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