宏循环扩展:抑制基酶的基质识别域
Wenshu Xu1, Yu Heng Lau2, Gerhard Fischer3
1Department of Pharmacology, University of Cambridge , Tennis Court Road, Cambridge CB2 1PD, United Kingdom.
Journal of the American Chemical Society
|January 14, 2017
概括
研究人员开发了一种新的双点击宏循环化方法,以制造基酶蛋白 (TNKS) 的制剂. 这些抑制剂通过破坏Wnt信号而没有传统PARP抑制剂的毒性,对癌症治疗具有前景.
科学领域:
- 医学化学
- 分子生物学
- 结构生物学
背景情况:
- 坦基酶蛋白 (TNKS) 是各种癌症中涉及的Wnt信号的关键调节者.
- 抑制TNKS是一种治疗策略,但目前的PARP催化抑制剂存在挑战.
- 针对TNKS独特的基质识别领域提供了另一种治疗方法.
研究的目的:
- 开发针对TNKS基质识别域的受约束抑制剂.
- 使用双点击宏循环化策略进行组合性设计.
- 为了提高特异性和稳定性,制造非螺旋或扩展形状的抑制剂.
主要方法:
- 采用分离和链接器工程的两部分策略.
- 使用点击化学组合结体的组合组合.
- 基于晶体结构的优化连接器长度,刚性和附着位置.
- 评估了的亲和力,蛋白质溶解的稳定性和TNKS-Axin相互作用的功能抑制.
主要成果:
- 开发了对TNKS具有亚微分子亲和力的宏环化.
- 在设计的抑制剂中实现了高蛋白分解稳定性.
- 证实了TNKS-Axin相互作用和Wnt信号的抑制.
- 证实了双点击方法对非螺旋结构的有用性.
结论:
- 针对TNKS的宏环化是一种有前途的新型基质竞争性抑制剂.
- 这种方法有可能抑制癌症中的Wnt信号,从而改善治疗特征.
- 双点击宏循环化方法适用于设计涉及多种构成的蛋白-蛋白相互作用抑制剂.
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