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Inhibition of Autophagy by a Small Molecule through Covalent Modification of the LC3 Protein.
Fan, Shijie; Yue, Liyan; Wan, Wei; Zhang, Yuanyuan; Zhang, Bidong; Otomo, Chinatsu; Li, Quanfu; Lin, Tingting; Hu, Junchi; Xu, Pan; Zhu, Mingrui; Tao, Hongru; Chen, Zhifeng; Li, Lianchun; Ding, Hong; Yao, Zhiyi; Lu, Junyan; Wen, Yi; Zhang, Naixia; Tan, Minjia; Chen, Kaixian; Xie, Yuli; Otomo, Takanori; Zhou, Bing; Jiang, Hualiang; Dang, Yongjun; Luo, Cheng.
Afiliação
  • Fan S; The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Yue L; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
  • Wan W; The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Zhang Y; The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Zhang B; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
  • Otomo C; The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Li Q; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
  • Lin T; The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Hu J; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
  • Xu P; Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
  • Zhu M; The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Tao H; School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai, 201210, China.
  • Chen Z; Center for Novel Target and Therapeutic Intervention, Institute of Life Sciences, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong District, Chongqing, China.
  • Li L; The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Ding H; The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Yao Z; The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Lu J; The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Wen Y; The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Zhang N; The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Tan M; Suzhou Autopharm, 108 Yuxin Road, Jiangsu, 215123, China.
  • Chen K; The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Xie Y; The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Otomo T; The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Zhou B; The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Jiang H; The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Dang Y; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
  • Luo C; Suzhou Autopharm, 108 Yuxin Road, Jiangsu, 215123, China.
Angew Chem Int Ed Engl ; 60(50): 26105-26114, 2021 12 06.
Article em En | MEDLINE | ID: mdl-34590387
ABSTRACT
The autophagic ubiquitin-like protein LC3 functions through interactions with LC3-interaction regions (LIRs) of other autophagy proteins, including autophagy receptors, which stands out as a promising protein-protein interaction (PPI) target for the intervention of autophagy. Post-translational modifications like acetylation of Lys49 on the LIR-interacting surface could disrupt the interaction, offering an opportunity to design covalent small molecules interfering with the interface. Through screening covalent compounds, we discovered a small molecule modulator of LC3A/B that covalently modifies LC3A/B protein at Lys49. Activity-based protein profiling (ABPP) based evaluations reveal that a derivative molecule DC-LC3in-D5 exhibits a potent covalent reactivity and selectivity to LC3A/B in HeLa cells. DC-LC3in-D5 compromises LC3B lipidation in vitro and in HeLa cells, leading to deficiency in the formation of autophagic structures and autophagic substrate degradation. DC-LC3in-D5 could serve as a powerful tool for autophagy research as well as for therapeutic interventions.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Autofagia / Bibliotecas de Moléculas Pequenas / Proteínas Associadas aos Microtúbulos Limite: Humans Idioma: En Revista: Angew Chem Int Ed Engl Ano de publicação: 2021 Tipo de documento: Article
Texto completo
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PubMed Links
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Autofagia / Bibliotecas de Moléculas Pequenas / Proteínas Associadas aos Microtúbulos Limite: Humans Idioma: En Revista: Angew Chem Int Ed Engl Ano de publicação: 2021 Tipo de documento: Article