聚合内源性蛋白质标记和招募用于诱导近距离疗法的可扩展发现效应因子
Yevgeniy V Serebrenik1,2, Deepak Mani1,2, Timothé Maujean3,4,5
1Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Research square
|October 4, 2023
概括
诱导接近疗法正在进步,但需要可扩展的工具. 我们开发了SPOTLITES用于选新型效应蛋白,从而实现针对性蛋白质降解和诱导近距离应用的高吞吐量发现.
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:
- 诱导接近疗法为药物开发提供了一个有前途的途径.
- 目前用于识别效应器-标蛋白对的方法在可扩展性和公正探索方面是有限的.
研究的目的:
- 开发和验证一种可扩展的平台,用于对内源性蛋白质-蛋白质相互作用进行高通量选.
- 通过诱导近距离来识别用于向蛋白质降解的新型效应蛋白.
- 扩大基于近距离的治疗策略的工具包.
主要方法:
- 结合可扩展的聚合准与可结合的标签在内源性站点 (SPOTLITES) 的高通量内源性蛋白质标记.
- 利用基于小分子的通用蛋白质招募来选基于近距离的效应因子.
- 采用两个直角屏幕用于向蛋白质降解,一个监测光,另一个监测细胞生长表型.
主要成果:
- 确定了许多潜在的新效应蛋白,用于有针对性的降解.
- 汇聚在CTLH复合体的成员上,作为蛋白质降解的强有力的诱导剂.
- 证明了SPOTLITES平台在发现新型降解因子方面的有效性.
结论:
- 引入了一个平台,用于聚合诱导内源性蛋白质蛋白质相互作用.
- 扩展了对向蛋白质降解和诱导接近的效应蛋白的工具集.
- 促进了对效应剂-标蛋白对进行治疗应用的系统探索.
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