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A Proximity-Triggered Strategy toward Transferable proteolysis targeting chimeras

CCS Chemistry 2023年第6期5卷 1433-1442页

作者： Yuena Wang Rongtong Zhao Chuan Wan Wei Kang Rui Wang Chengyao Chiang Xiaochun Guo Qi Chang Zhanfeng Hou Yuxin Ye Qinhong Luo Ziyuan Zhou Jianbo Liu Shuiming Li Dongyuan Wang Feng Yin Zigang Li State Key Laboratory of Chemical Oncogenomics School of Chemical Biology and BiotechnologyPeking University Shenzhen Graduate SchoolShenzhen 518055 Shenzhen Bay Laboratory Shenzhen 518055 Pingshan Translational Medicine Center Shenzhen Bay LaboratoryShenzhen 518055 Guangdong Provincial Key Laboratory of Regional Immunity and Diseases Shenzhen University International Cancer CenterDepartment of Cell Biology and GeneticsSchool of MedicineShenzhen UniversityShenzhen 518055 Shenzhen Key Laboratory of Microbiology and Gene Engineering Shenzhen UniversityShenzhen 518055 Department of Pharmacy Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030

Over the past 20 years,great efforts have been invested in developing site-specific approaches to protein modification to dissect protein functions directly and ***,we report a proximitytriggered group transfer strategy from a sulfonium warhead to a Cysteine(Cys)residue of the target *** a guiding ligand,cargoes could be transferred selectively from a sulfonium center onto the Cys residue in the vicinity of their binding *** successful thalidomide transfer of sulfonium 1-X could be applied intracellularly for epidermal growth factor receptor degradation,highlighting the potential of group transfer strategy as a suite of chemical biology studies,including cell imaging,protein profiling,and protein degradation by simply employing different transferrable groups.

关键词： sulfonium protein covalent modification proteolysis targeting chimeras site-specific modification degradation

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Applications and prospects of cryo-EM in drug discovery

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Military Medical Research 2023年第6期10卷 848-861页

作者： Kong-Fu Zhu Chuang Yuan Yong-Ming Du Kai-Lei Sun Xiao-Kang Zhang Horst Vogel Xu-Dong Jia Yuan-Zhu Gao Qin-Fen Zhang Da-Ping Wang Hua-Wei Zhang Department of Biomedical Engineering Southern University of Science and TechnologyShenzhen 518055GuangdongChina Department of Biochemistry and Molecular Biology School of Basic Medical SciencesPeking UniversityBeijing 100191China Department of Structural Biology St.Jude Children’s Research HospitalMemphisTN 38105USA Center for Protein Science and Crystallography School of Life SciencesFaculty of ScienceChinese University of Hong KongHong Kong 999077China Interdisciplinary Center for Brain Information the Brain Cognition and Brain Disease InstituteShenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055GuangdongChina Faculty of Life and Health Sciences Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055GuangdongChina Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions Shenzhen 518055GuangdongChina Shenzhen Institute of Advanced Technology Chinese Academy of SciencesShenzhen 518055GuangdongChina State Key Lab for Biocontrol School of Life SciencesSun Yat-Sen UniversityGuangzhou 510275China Cryo‑EM Facility Center Southern University of Science and TechnologyShenzhen 518055GuangdongChina Department of Orthopedics Shenzhen Intelligent Orthopaedics and Biomedical Innovation PlatformGuangdong Provincial Research Center for Artifcial Intelligence and Digital Orthopedic TechnologyShenzhen Second People’s HospitalThe First Affiliated Hospital of Shenzhen UniversityShenzhen 518000GuangdongChina Guangdong Provincial Key Laboratory of Advanced Biomaterials Southern University of Science and TechnologyShenzhen 518055GuangdongChina

Drug discovery is a crucial part of human healthcare and has dramatically benefited human lifespan and life quality in recent centuries, however, it is usually time-and effort-consuming. Structural biology has been demonstrated as a powerful tool to accelerate drug development. Among different techniques, cryo-electron microscopy(cryo-EM) is emerging as the mainstream of structure determination of biomacromolecules in the past decade and has received increasing attention from the pharmaceutical industry. Although cryo-EM still has limitations in resolution, speed and throughput, a growing number of innovative drugs are being developed with the help of cryo-EM. Here, we aim to provide an overview of how cryo-EM techniques are applied to facilitate drug discovery. The development and typical workflow of cryo-EM technique will be briefly introduced, followed by its specific applications in structure-based drug design, fragment-based drug discovery, proteolysis targeting chimeras, antibody drug development and drug repurposing. Besides cryo-EM, drug discovery innovation usually involves other state-of-the-art techniques such as artificial intelligence(AI), which is increasingly active in diverse areas. The combination of cryo-EM and AI provides an opportunity to minimize limitations of cryo-EM such as automation, throughput and interpretation of mediumresolution maps, and tends to be the new direction of future development of cryo-EM. The rapid development of cryo-EM will make it as an indispensable part of modern drug discovery.

关键词： Cryo-electron microscopy(cryo-EM) Drug discovery Structure-based drug design Fragment-based drug discovery proteolysis targeting chimeras Drug repurposing Artificial intelligence(AI)

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