Inhibition of Autophagy by a Small Molecule through Covalent Modification of the LC3 Protein,Angewandte Chemie International Edition

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Inhibition of Autophagy by a Small Molecule through Covalent Modification of the LC3 Protein
Angewandte Chemie International Edition ( IF 16.1 ) Pub Date : 2021-09-29 , DOI: 10.1002/anie.202109464
Shijie Fan _{1,

2} , Liyan Yue ₁ , Wei Wan _{1,

2} , Yuanyuan Zhang _{1,

2} , Bidong Zhang ₁ , Chinatsu Otomo ₃ , Quanfu Li ₄ , Tingting Lin _{1,

5} , Junchi Hu ₆ , Pan Xu ₁ , Mingrui Zhu ₁ , Hongru Tao ₁ , Zhifeng Chen ₁ , Lianchun Li ₁ , Hong Ding ₁ , Zhiyi Yao ₇ , Junyan Lu ₁ , Yi Wen ₁ , Naixia Zhang ₁ , Minjia Tan ₁ , Kaixian Chen _{1,

2} , Yuli Xie ₇ , Takanori Otomo ₃ , Bing Zhou ₈ , Hualiang Jiang _{1,

2} , Yongjun Dang _{4,

6} , Cheng Luo _{1,

2,

5,

9,

10}

Affiliation

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.
University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
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.
School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai, 201210, China.
Center for Novel Target and Therapeutic Intervention, Institute of Life Sciences, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong District, Chongqing, China.
Suzhou Autopharm, 108 Yuxin Road, Jiangsu, 215123, China.
Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
School of Pharmacy, Fudan University, Shanghai, 201203, China.
School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.

A potent probe, DC-LC3in-D5, was discovered which demonstrates high selectivity to LC3A/B in the proteome. DC-LC3in-D5 inhibits autophagy by attenuating LC3B lipidation, which subsequently reduces the extent of autophagic structure formation and later substrate degradation.