期刊
SCIENCE
卷 348, 期 6231, 页码 239-242出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aaa4484
关键词
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资金
- Medical Research Council (UK)
- European Research Council (ERC) under the European Union/ERC [309516]
- European Molecular Biology Organization and Human Frontier Science Program
- Swiss National Science Foundation
- Italian Ministry of Health [GR-2011-02642791]
- NIH [R01-NS55256]
- European Research Council (ERC) [309516] Funding Source: European Research Council (ERC)
- MRC [MC_U105185860] Funding Source: UKRI
- Medical Research Council [MC_U105185860] Funding Source: researchfish
Protein phosphorylation regulates virtually all biological processes. Although protein kinases are popular drug targets, targeting protein phosphatases remains a challenge. Here, we describe Sephin1 (selective inhibitor of a holophosphatase), a small molecule that safely and selectively inhibited a regulatory subunit of protein phosphatase 1 in vivo. Sephin1 selectively bound and inhibited the stress-induced PPP1R15A, but not the related and constitutive PPP1R15B, to prolong the benefit of an adaptive phospho-signaling pathway, protecting cells from otherwise lethal protein misfolding stress. In vivo, Sephin1 safely prevented the motor, morphological, and molecular defects of two otherwise unrelated protein-misfolding diseases in mice, Charcot-Marie-Tooth 1B, and amyotrophic lateral sclerosis. Thus, regulatory subunits of phosphatases are drug targets, a property exploited here to safely prevent two protein misfolding diseases.
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