国家纳米中心王海团队提出了基于碳点的PROTACs靶向降解PD-L1和激活STING通路用于癌症免疫治疗。相关研究成果于2023年1月17日发表在《德国应用化学》。

蛋白质水解靶向嵌合体（PROTACs）技术是降解疾病相关蛋白的一种新兴方法。

该文中，研究人员报道了一种基于碳点（CD）的PROTAC（CDTAC），它通过泛素蛋白酶体系统降解膜蛋白。CDTACs可以与程序性细胞死亡配体1（PD-L1）结合，吸收cereblon蛋白（CRBN）诱导PD-L1泛素化，并用蛋白酶体降解它们。模拟禁食饮食（FMD）也用于增强细胞摄取和蛋白酶体活性。CDTACs可分别降解CT26或B16-F10肿瘤细胞中99%或90%以上的PD-L1。此外，CDTACs可以激活干扰素基因刺激因子（STING）途径以触发免疫应答。因此，CDTACs联合FMD治疗有效抑制CT26和B16-F10肿瘤的生长。与基于小分子的PROTACs相比，CDTACs具有许多优点，如有效的膜蛋白降解、靶向肿瘤积聚、免疫系统激活和体内检测。

附：英文原文

Title: Targeted Degradation of PD-L1 and Activation of the STING Pathway by Carbon-Dot-Based PROTACs for Cancer Immunotherapy

Author: Wen Su, Mixiao Tan, Zhihang Wang, Jie zhang, Wenping huang, Haohao Song, Xingye Wang, Haitao Ran, Yanfeng Gao, Guangjun Nie, Hai Wang

Issue&Volume: 2023-01-17

Abstract: Proteolysis targeting chimeras (PROTACs) technology is an emerging approach to degrade disease-associated proteins. Here, we report a carbon-dot (CD)-based PROTAC (CDTAC) that degrade membrane proteins via ubiquitin-proteasome system. CDTACs can bind to programmed cell death ligand 1 (PD-L1), recruit cereblon (CRBN) to induce PD-L1 ubiquitination, and degrade them with proteasomes. Fasting-mimicking diet (FMD) is also used to enhance the cellular uptake and proteasome activity. More than 99% or 90% of PD-L1 in CT26 or B16-F10 tumor cells can be degraded by CDTACs, respectively. Furthermore, CDTACs can activate the stimulator of interferon genes (STING) pathway to trigger immune responses. Thus, CDTACs with FMD treatment effectively inhibit the growth of CT26 and B16-F10 tumors. Compared with small molecule-based PROTACs, CDTACs offer several advantages, such as efficient membrane protein degradation, targeted tumor accumulation, immune system activation, and in vivo detection.

DOI: 10.1002/anie.202218128

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202218128