通过DNA框架设计的嵌合体平台,可以选择性地向蛋白质降解
Li Zhou1, Bin Yu2, Mengqiu Gao1
1Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 210009, China.
Nature communications
|July 26, 2023
概括
研究人员开发了基于DNA框架的PROTACs (DbTACs),用于精确的蛋白质降解. 这种通用平台可以实现高通量合成和可调节的配体间距,以实现高效和选择性的目标耗尽.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- 开发针对蛋白质分解的嵌合体 (PROTACs) 需要一个通用平台来精确降解感兴趣的蛋白质 (POI).
- 现有的 PROTAC 开发面临广泛适用性和高效合成方面的挑战.
研究的目的:
- 使用DNA框架为PROTAC开发设计一个通用平台.
- 为了证明基于DNA框架的PROTACs (DbTACs) 在向蛋白质降解中的有效性.
主要方法:
- 利用DNA四面体作为POI和E3结合酶连接体的精确空间排列的刚性模板.
- 采用简单的生物对角化学和自组装,用于DbTACs的高吞吐量合成.
- 操纵了从8 Å到57 Å的配体间距,并测试了各种弹头 (小分子,抗体,DNA动机).
主要成果:
- 具有优化链接长度的DbTAC显示降解率和结合亲和力增加.
- 双特异性DbTACs可实现多目标耗尽和蛋白质亚型的选择性降解.
- DbTACs在降解各种细胞区中的各种酶和转录因子等目标方面表现出强大的有效性.
结论:
- 模块化DNA框架为PROTAC开发中的合基质提供了一个通用平台.
- DbTAC提供了对一般降解剂设计原则的见解,并为药物发现提供了有前途的战略.
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