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
  • 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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