AUTACs: Cargo-Specific Degraders Using Selective Autophagy

Daiki Takahashi, Jun Moriyama, Tomoe Nakamura, Erika Miki, Eriko Takahashi, Ayami Sato, Takaaki Akaike, Kaori Itto-Nakama, Hirokazu Arimoto

研究成果: Article査読

56 被引用数 (Scopus)

抄録

Protein silencing represents an essential tool in biomedical research. Targeted protein degradation (TPD) strategies exemplified by PROTACs are rapidly emerging as modalities in drug discovery. However, the scope of current TPD techniques is limited because many intracellular materials are not substrates of proteasomal clearance. Here, we described a novel targeted-clearance strategy (autophagy-targeting chimera [AUTAC]) that contains a degradation tag (guanine derivatives) and a warhead to provide target specificity. As expected from the substrate scope of autophagy, AUTAC degraded fragmented mitochondria as well as proteins. Mitochondria-targeted AUTAC accelerated both the removal of dysfunctional fragmented mitochondria and the biogenesis of functionally normal mitochondria in patient-derived fibroblast cells. Cytoprotective effects against acute mitochondrial injuries were also seen. Canonical autophagy is viewed as a nonselective bulk decomposition system, and none of the available autophagy-inducing agents exhibit useful cargo selectivity. With its target specificity, AUTAC provides a new modality for research on autophagy-based drugs.

本文言語English
ページ(範囲)797-810.e10
ジャーナルMolecular Cell
76
5
DOI
出版ステータスPublished - 2019 12 5

ASJC Scopus subject areas

  • 分子生物学
  • 細胞生物学

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