Artificial Nucleic Acid Tractor-Directed Simultaneous Depletion of Oncogenic Membrane Proteins Without Hijacking Proteolysis-Specific Actuator  

作　　者：Zhen Zou Songlan Pan Qian Xue Ting Chen Ziyun Huang Bei Qing Pengfei Liu Conghui Zhao Yunlin Sun Erhu Xiong Ronghua Yang 

机构地区：[1]Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research,Ministry of Education,College of Chemistry and Chemical Engineering,Hunan Normal University,Changsha 410081 [2]School of Chemistry and Chemical Engineering,Hunan Provincial Key Laboratory of Cytochemistry,Changsha University of Science and Technology,Changsha 410114 [3]The Second Xiangya Hospital,Central South University,Changsha 410011

出　　处：《CCS Chemistry》2024年第2期439-449,共11页中国化学会会刊（英文）

基　　金：supported in part by the National Natural Science Foundation of China(grant nos.21705010,21735001,22274046,and 91853104);Hunan Provincial Natural Science Foundation of China(grant nos.2022JJ20038 and 2020JJ4409);the Scientific Research Fund of Hunan Provincial Education Department(grant no.20B032);Natural Science Foundation of Changsha City(grant no.kq2202189).

摘　　要：Targeted protein degradation(TPD)is an emerging tool for degrading proteins of interest,which affords an attractive modality for cancer therapy.However,the present TPD technologies must engage a proteolysis-specific actuator to initiate degradation of targeted proteins in the proteasome or lysosome.Herein,we report an artificial tractor that can induce endocytosis-mediated protein depletion without hijacking a proteolysis-specific actuator.In this design,bispecific aptamer chimeras(BSACs)are established,which can bridge human epidermal growth factor receptor 2(ErbB-2),an important biomarker in a common important biomarker in cancer,with membrane proteins of interest.Taking advantage of the property of aptamer-induced endocytosis and digestion of ErbB-2,another membrane protein is translocated into the lysosome in a hitchhike-like manner,resulting in lysosomal proteolysis along with ErbB-2.This strategy frees the TPD from the fundamental limitation of proteolysis-specific actuator and allows simultaneous regulation of the quantity and function of two oncogenic receptors in a cell-type-specific manner,expanding the application scope of TPD-based therapeutics.

关 键 词：targeted protein degradation APTAMER epidermal growth factor receptor 2 LYSOSOME membrane proteins cancer therapy 

分 类 号：R730[医药卫生—肿瘤]