Persistent Degradation of HER2 Protein by Hybrid nanoPROTAC for Programmed Cell Death

作者全名："Wang, Zhihang; Tan, Mixiao; Su, Wen; Huang, Wenping; Zhang, Jie; Jia, Fuhao; Cao, Guoliang; Liu, Xinyang; Song, Haohao; Ran, Haitao; Nie, Guangjun; Wang, Hai"

作者地址："[Wang, Zhihang; Su, Wen; Huang, Wenping; Zhang, Jie; Jia, Fuhao; Cao, Guoliang; Liu, Xinyang; Song, Haohao; Nie, Guangjun; Wang, Hai] Natl Ctr Nanosci & Technol, CAS Key Lab Biomed Effects Nanomat & Nanosafety, Beijing 100190, Peoples R China; [Wang, Zhihang; Su, Wen; Huang, Wenping; Zhang, Jie; Jia, Fuhao; Cao, Guoliang; Liu, Xinyang; Song, Haohao; Ran, Haitao; Nie, Guangjun; Wang, Hai] Natl Ctr Nanosci & Technol, CAS Ctr Excellence Nanosci, Beijing 100190, Peoples R China; [Wang, Zhihang; Tan, Mixiao; Huang, Wenping; Zhang, Jie; Jia, Fuhao; Wang, Hai] Univ Chinese Acad Sci, Beijing 100049, Peoples R China; [Tan, Mixiao; Ran, Haitao] Chongqing Med Univ, Affiliated Hosp 2, Chongqing 400010, Peoples R China; [Tan, Mixiao; Ran, Haitao] Chongqing Key Lab Ultrasound Mol Imaging, Chongqing 400010, Peoples R China"

通信作者："Wang, H (通讯作者)，Natl Ctr Nanosci & Technol, CAS Key Lab Biomed Effects Nanomat & Nanosafety, Beijing 100190, Peoples R China.; Ran, HT; Wang, H (通讯作者)，Natl Ctr Nanosci & Technol, CAS Ctr Excellence Nanosci, Beijing 100190, Peoples R China.; Wang, H (通讯作者)，Univ Chinese Acad Sci, Beijing 100049, Peoples R China.; Ran, HT (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Chongqing 400010, Peoples R China.; Ran, HT (通讯作者)，Chongqing Key Lab Ultrasound Mol Imaging, Chongqing 400010, Peoples R China."

来源：JOURNAL OF MEDICINAL CHEMISTRY

ESI学科分类：CHEMISTRY

WOS号：WOS:000981625600001

JCR分区：Q1

影响因子：7.3

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：　

摘要："Proteolysis-targeting chimera (PROTAC) has emerged as a promising strategy for degrading proteins of interest. Peptide-based PROTACs offer several advantages over small molecule-based PROTACs, such as high specificity, low toxicity, and large protein-protein interaction surfaces. However, peptide-based PROTACs have several intrinsic shortcomings that strongly limit their application including poor cell permeability and low stability and potency. Herein, we designed a nanosized hybrid PROTAC (GNCTACs) to target and degrade human epidermal growth factor receptor 2 (HER2) in tumor cells. Gold nanoclusters (GNCs) were utilized to connect HER2-targeting peptides and cereblon (CRBN)-targeting ligands. GNCTACs could overcome the intrinsic barriers of peptide-based PROTACs, efficiently delivering HER2targeting peptides in the cytoplasm and protecting them from degradation. Furthermore, a fasting mimicking diet was applied to enhance the cellular uptake and proteasome activity. Consequently, more than 95% of HER2 in SKBR3 cells was degraded by GNCTACs, and the degradation lasted for at least 72 h, showing a catalytic-like reaction."

基金机构："Key Area R&D Program of Guangdong Province [2020B0101020004]; NSFC [31971307]; Start-up Foundation of NCNST, CAS"

基金资助正文："This work was financially supported by the Key Area R & D Program of Guangdong Province (2020B0101020004), NSFC (31971307), and the Start-up Foundation of NCNST, CAS. We thank the Core Facility of Center of Biomedical Analysis, Tsinghua University, for assistance with confocal microscopy."