研究动态
Articles below are published ahead of final publication in an issue. Please cite articles in the following format: authors, (year), title, journal, DOI.

通过分离混合脂质体蛋白酶降解靶向嵌合物方法进行选择性蛋白质降解。

Selective Protein of Interest Degradation through the Split-and-Mix Liposome Proteolysis Targeting Chimera Approach.

发表日期:2023 Sep 14
作者: Chunli Song, Zijun Jiao, Zhanfeng Hou, Rui Wang, Chenshan Lian, Yun Xing, Qinhong Luo, Yuhao An, Fenfang Yang, Yuechen Wang, Xinrui Sha, Zhijun Ruan, Yuxin Ye, Zhihong Liu, Zigang Li, Feng Yin
来源: Protein & Cell

摘要:

蛋白酶效应靶向嵌合物(PROTAC)技术代表了一种应用细胞内泛素-蛋白酶体系统进行靶蛋白降解的有希望的新方法。最近,我们基于肽自组装开发了一种分离与混合纳米平台,可作为自调节平台用于多功能应用。然而,药物效力的降低限制了肽基SM-PROTAC进一步的生物医药应用。在本研究中,我们开发了一种基于脂质体自组装(LipoSM-PROTAC)的新型分离与混合PROTAC系统,并与FA(叶酸)进行改性以增强其靶向肿瘤的能力。选择雌激素受体(ERα)作为感兴趣的蛋白质(POI)来验证Lipo降解酶效性。结果表明,该PROTAC能够高效且选择性地被FA受体阳性细胞(FR+)内摄取,并以显著降低的浓度降解POI。与基于肽的SM-PROTAC相比,我们设计的LipoSM-PROTAC系统能够以更低的浓度实现治疗效果,并为临床转化潜力提供机会。总体而言,基于脂质体的平台展现了更高的药物效力,为PROTAC和其他生物分子调控提供了有前景的应用潜力。
Proteolysis Targeting Chimera (PROTAC) technology represents a promising new approach for target protein degradation using a cellular ubiquitin-proteasome system. Recently, we developed a split-and-mix nanoplatform based on peptide self-assembly, which could serve as a self-adjustable platform for multifunctional applications. However, the lower drug efficacy limits further biomedical applications of peptide-based SM-PROTAC. In this study, we develop a novel split-and-mix PROTAC system based on liposome self-assembly (LipoSM-PROTAC), concurrent with modification of FA (folate) to enhance its tumor-targeting capabilities. Estrogen receptors (ERα) were chosen as the protein of interest (POI) to validate the efficacy of Lipo degraders. Results demonstrate that this PROTAC can be efficiently and selectively taken up into the cells by FA receptor-positive cells (FR+) and degrade the POI with significantly reduced concentration. Compared to the peptide-based SM-PROTACs, our designed LipoSM-PROTAC system could achieve therapeutic efficacy with a lower concentration and provide opportunities for clinical translational potential. Overall, the LipoSM-based platform shows a higher drug efficacy, which offers promising potential applications for PROTAC and other biomolecule regulations.