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Proteasomal and lysosomal degradation for specific and durable suppression of immunotherapeutic targets

Cancer Biology & Medicine 2020年第3期17卷 583-598页

作者： Yungang Wang Shouyan Deng Jie Xu Institutes of Biomedical Sciences Zhongshan-Xuhui Hospitaland Shanghai Key Laboratory of Medical EpigeneticsFudan UniversityShanghai 200433China Department of Laboratory Medicine The First People's Hospital of Yancheng CityYancheng 224006China Renji Hospital School of MedicineShanghai Jiao Tong UniversityShanghai 200127China

Cancer immunotherapy harness the body's immune system to eliminate cancer,by using a broad panel of soluble and membrane proteins as therapeutic *** signaling mediated by ligand-receptor interaction may be blocked by monoclonal antibodies,but because of repopulation of the membranevia intracellular organelles,targets must be eliminated in whole *** protein degradation,as exemplified in proteolysis targeting chimera(PROTAC)studies,is a promising strategy for selective inhibition of target *** recently reported use of lysosomal targeting molecules to eliminate immune checkpoint proteins has paved the way for targeted degradation of membrane proteins as crucial anti-cancer *** studies on these molecules'modes of action,target-binding"warheads",lysosomal sorting signals,and linker design should facilitate their rational *** and derivatives may improve their cell-penetrating ability and thein vivo stability of these *** studies suggest the promise of alternative strategies for cancer immunotherapy,with the aim of achieving more potent and durable suppression of tumor ***,the successes and limitations of antibody inhibitorsin cancer immunotherapy,as well as research progress on PROTAC-and lysosomal-dependent degradation of target proteins,are reviewed.

关键词： Cancer immunotherapy membrane protein PROTAC targeted degradation

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Proteolysis targeting chimera technology:a novel strategy for treating diseases of the central nervous system

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Neural Regeneration Research 2021年第10期16卷 1944-1949页

作者： Ke Ma Xiao-Xiao Han Xiao-Ming Yang Song-Lin Zhou Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury RepairCo-Innovation Center of NeuroregenerationNantong UniversityNantongJiangsu ProvinceChina College of Life Science Nantong UniversityNantongJiangsu ProvinceChina

Neurological diseases such as stroke,Alzheimer’s disease,Parkinson’s disease,and Huntington’s disease are among the intractable diseases for which appropriate drugs and treatments are *** targeting chimera(PROTAC)technology is a novel strategy to solve this *** technology uses the ubiquitin-protease system to eliminate mutated,denatured,and harmful proteins in *** can be reused,and utilizes the protein destruction mechanism of the cells,thus making up for the deficiencies of traditional protein degradation *** can effectively target and degrade proteins,including proteins that are difficult to identify and ***,it has extremely important implications for drug development and the treatment of neurological *** present,the targeted degradation of mutant BTK,mHTT,Tau,EGFR,and other proteins using PROTAC technology is gaining *** is expected that corresponding treatment of nervous system diseases can be *** review first focuses on the recent developments in PROTAC technology in terms of protein degradation,drug production,and treatment of central nervous system diseases,and then discusses its *** review will provide a brief overview of the recent application of PROTAC technology in the treatment of central nervous system diseases.

关键词： Alzheimer’s disease disease treatment drug development Huntington’s disease proteolysis targeting chimera stroke targeted degradation

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Autophagic Clearance of Lipid Droplets Alters Metabolic Phenotypes in a Genetic Obesity–Diabetes Mouse Model

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Phenomics 2023年第2期3卷 119-129页

作者： Ningxie Chen Boxun Lu Yuhua Fu State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science School of Life SciencesFudan UniversityShanghai 200438China

Lipid droplets(LDs)are intracellular organelles that store neutral lipids,and their aberrant accumulation is associated with many diseases including metabolic disorders such as obesity and ***,the potential pathological contribu-tions of LDs in these diseases are unclear,likely due to a lack of chemical biology tools to clear *** recently developed LD-clearance small molecule compounds,Lipid Droplets·AuTophagy TEthering Compounds(LD·ATTECs),that are able to induce autophagic clearance of LDs in cells and in the liver of db/db(C57BL/6J Leprdb/Leprdb)mouse model,which is a widely used genetic model for obesity–***,the potential effects on the metabolic phenotype remain to be ***,using the metabolic cage assay and the blood glucose assay,we performed phenotypic characteriza-tion of the effects of the autophagic degradation of LDs by LD·ATTECs in the db/db mouse *** study reveals that LD·ATTECs increased the oxygen uptake of mice and the release of carbon dioxide,enhanced the heat production of animals,partially enhanced the exercise during the dark phase,decreased the blood glucose level and improved insulin ***,the study characterized the metabolic phenotypes induced by LD·ATTECs in an obesity–diabetes mouse model,revealing novel functional impacts of autophagic clearance of LDs and providing insights into LD biology and obesity–dia-betes pathogenesis from the phenotypic perspective.

关键词： Lipid droplets Autophagy Obesity–diabetes LD ATTECs targeted degradation Metabolic cages

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Perspectives of autophagy-tethering compounds(ATTECs)in drug discovery

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医学+（英文） 2024年第1期1卷 84-106页

作者： Yu Ding Dong Xing Yiyan Fei Shouqing Luo Boxun Lu State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science School of Life SciencesFudan UniversityShanghai 200438China Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development School of Chemistry and Molecular EngineeringEast China Normal UniversityShanghai 200062China Department of Optical Science and Engineering Shanghai Engineering Research Center of Ultra-Precision Optical ManufacturingKey Laboratory of Micro and Nano Photonic Structures(Ministry of Education)Fudan UniversityShanghai 200433China Peninsula Schools of Medicine and Dentistry Institute of Translational and Stratified MedicineUniversity of PlymouthPlymouth PL68BUUK

Degrader technologies provide unprecedented strategies to tackle diseases caused by pathogenic proteins that are difficult to target by the traditional inhibitor *** pioneering technology,proteolysis-targeting chimera(PROTAC),has re-volutionized small-molecule drug ***,PROTACs hijack the ubiqui-tination-proteasome pathway,which is incapable of degrading certain categories of *** address this limitation,scientists introduced autophagy-tethering com-pounds(ATTECs),capitalizing on the autophagosome protein LC3 to selectively break down both pathogenic proteins and *** review explores multiple dimensions of ATTECs,focusing on their mechanisms of action and potential appli-cations in drug discovery.

关键词： Autophagy Degrader targeted degradation Drug discovery High-throughput screening LC3

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