Friday, October 8, 2021

Inhibition of autophagy by a small molecule through covalent modification of LC3

Cheng Luo, Shijie Fan, Liyan Yue, Wei Wan, Yuanyuan Zhang, Bidong Zhang, Chinatsu Otomo, Quanfu Li, Tingting Lin, Junchi Hu, Pan Xu, Mingrui Zhu, Hongru Tao, Zhifeng Chen, Lianchun Li, Hong Ding, Zhiyi Yao, Junyan Lu, Yi Wen, Naixia Zhang, Minjia Tan, Kaixian Chen, Yuli Xie, Takanori Otomo, Bing Zhou, Hualiang Jiang, Yongjun Dang

Angew. Chem. Int. Ed. 2021

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 the interface. Through screening covalent compounds, we discover 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.

Covalent drug discovery using sulfur(VI) fluoride exchange warheads

Huang Huang, Lyn H. Jones Expert Opinion on Drug Discovery , 2023 Covalent drug discovery has ...