硫酶诱导的抗瘤Supra-PROTACs的现场配方
Ninglin Chen1,2, Zeyu Zhang1, Xin Liu1
1Key Laboratory of Functional Polymer Materials, Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Institute of Polymer Chemistry, College of Chemistry, Nankai University, 94 Weijin Road, Tianjin 300071, China.
Journal of the American Chemical Society
|April 5, 2024
概括
研究人员开发了Supra-PROTACs,可以在癌细胞内组装,改善向蛋白质降解,以加强癌症治疗. 这种创新方法可以提高药物输送效率,同时保持生物安全性.
科学领域:
- 生物化学
- 分子生物学
- 癌症治疗
背景情况:
- 蛋白质溶解向嵌合体 (PROTAC) 技术提供了一种新的癌症治疗策略.
- 目前PROTAC的局限性包括不良的输送和不充分的蛋白质降解.
研究的目的:
- 使用细胞内酶反应性组件开发抗瘤Supra-PROTACs的现场配方策略.
- 提高PROTAC的向性,传递性和POI降解效率,以改善癌症治疗.
主要方法:
- 将硫化与乌比奎VHL和Bcl-xL的配体组合在一起,形成一个pro-Supra-PROTAC.
- 根据蛋白质结合亲和力优化配体比,以提高生物活性.
- 利用细胞内硫酶活性对癌细胞中的纳米纤维Supra- PROTAC进行酶反应组合.
主要成果:
- 在硫酸酶过度表达的癌细胞中,Pro- Supra- PROTACs组合成Supra- PROTACs.
- Supra- PROTACs通过Bcl- xL降解和酶依赖的亡诱导癌细胞毒性.
- 在体内研究表明瘤积累,保留和瘤生长抑制有很好的生物安全性.
结论:
- 这项研究提出了一种新的酶调节组合方法,用于活细胞中的Supra- PROTAC配方.
- 这一战略显著提高了PROTAC的目标交付和POI降解效率.
- 开发的Supra- PROTAC显示出有效和安全的癌症治疗潜力,特别是与化疗药物结合使用时.
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