Targeted Degradation of Alpha-Synuclein by Autophagosome-Anchoring Chimera Peptides

• Published in: Journal of medicinal chemistry 2023-09, Vol.66 (17), p.12614-12628
• Main Authors: Tong, Yichen, Zhu, Wentao, Chen, Jian, Zhang, Wenqian, Xu, Fang, Pang, Jiyan
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c01303

Targeted protein degradation (TPD) confers knockdown of “undruggable” targets such as alpha-synuclein (αSyn), a pathogenic protein in multiple neurodegenerative diseases. Though many of these proteins were mainly degraded through the autophagy-lysosome pathway (ALP), few TPD tools harnessing the ALP were reported. Herein, we developed a strategy termed autophagosome-anchoring chimera (ATACC), in which the protein of interest (POI) can be anchored to microtubule-associated protein-1 light chain-3B (LC3B) on the autophagosome with the assistance of an LC3-interacting region (LIR)-containing bifunctional peptide, and the selective autophagy of the POI is thus facilitated. A series of αSyn-targeting ATACC peptides were designed and synthesized. Biological evaluations demonstrated that these compounds could degrade αSyn specifically and effectively through a “chemical-induced cargo recognition–ALP degradation” mechanism. The neuroprotective effects of ATACC peptide P1 were further validated in vitro and in vivo. Collectively, our results provided a new TPD tool and revealed a potential therapeutic strategy against synucleinopathies.