一个超强的和选择性循环抑制人体β-因子XIIa在一个循环
Wenyu Liu1, Simon J de Veer2,3, Yen-Hua Huang2,3
1Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo, 113-0033, Japan.
Journal of the American Chemical Society
|November 1, 2021
概括
植物循环,通过mRNA显示被设计成强大的FXIIa抑制剂. 抑制剂cMCoFx1具有很高的选择性,为凝血障碍提供治疗潜力.
科学领域:
- 生物化学
- 分子生物学
- 药理学
背景情况:
- 环类是具有独特的循环结构和囊结的植物.
- 这些特性提供了稳定性和细胞透性,使它们成为有前途的药物.
- 由于它们的结构复杂性和对多种图书馆的需求,工程周期是具有挑战性的.
研究的目的:
- 开发一种基于循环的强效和选择性抑制剂的策略.
- 通过大规模查方法确定向XIIa因子 (FXIIa) 的抑制剂.
- 探索环氧化物作为药物开发的支架的治疗潜力.
主要方法:
- 使用mRNA显示技术从超过10^12个成员的库中选择抑制剂.
- 使用Momordica cochinchinensis试抑制剂-II (MCoTI-II) 循环架.
- 确定化合物对FXIIa和相关蛋白酶的抑制常数和选择性.
- 获得了与FXIIa结合的抑制剂的共晶结构.
主要成果:
- 成功选择了基于循环的强效FXIIa抑制剂.
- 确定cMCoFx1为最强效和选择性的抑制剂,具有皮科莫尔抑制常数.
- 对其他血清蛋白酶而言,FXIIa的选择性达到三级以上.
- 同晶体结构揭示了在接口的高亲和度结合相互作用.
结论:
- 开发的mRNA显示策略可以有效地设计基于循环的治疗方法.
- cMCoFx1通过FXIIa对内在凝固途径进行了特定的抑制.
- 环氧化物是治疗应用的有吸引力的多功能囊结支架.
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