2. Academic Validation
  3. Inhibition of Autophagy by a Small Molecule through Covalent Modification of the LC3 Protein

Inhibition of Autophagy by a Small Molecule through Covalent Modification of the LC3 Protein

  • Angew Chem Int Ed Engl. 2021 Dec 6;60(50):26105-26114. 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
Affiliations

Affiliations

  • 1 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.
  • 2 University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
  • 3 Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
  • 4 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.
  • 5 School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai, 201210, China.
  • 6 Center for Novel Target and Therapeutic Intervention, Institute of Life Sciences, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong District, Chongqing, China.
  • 7 Suzhou Autopharm, 108 Yuxin Road, Jiangsu, 215123, China.
  • 8 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.
  • 9 School of Pharmacy, Fudan University, Shanghai, 201203, China.
  • 10 School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
PMID: 34590387 DOI: 10.1002/anie.202109464
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.

Keywords

LC3; covalent modification; post-translational modification; probes; proteome.

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