論文

査読有り
2019年12月5日

AUTACs: Cargo-Specific Degraders Using Selective Autophagy

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

76
5
開始ページ
797
終了ページ
810.e10
記述言語
掲載種別
研究論文(学術雑誌)
DOI
10.1016/j.molcel.2019.09.009

© 2019 Elsevier Inc. 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.

リンク情報
DOI
https://doi.org/10.1016/j.molcel.2019.09.009
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/31606272
Scopus
https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85075578749&origin=inward
Scopus Citedby
https://www.scopus.com/inward/citedby.uri?partnerID=HzOxMe3b&scp=85075578749&origin=inward

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