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Design, Synthesis, and Bioactivity of Novel Bifunctional Small Molecules for Alzheimer’s disease
[Image: see text] The abnormal phosphorylation of the τ-protein is a typical early pathological feature of Alzheimer’s disease (AD). The excessive phosphorylation of the τ-protein in the brain causes the formation of neurofibrillary tangles (NFTs) and increases the neurotoxicity of amyloid-β (Aβ). T...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9352321/ https://www.ncbi.nlm.nih.gov/pubmed/35936449 http://dx.doi.org/10.1021/acsomega.2c02130 |
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author | Liang, Meihao Gu, Lili Zhang, Hongjie Min, Jingli Wang, Zunyuan Ma, Zhen Zhang, Chixiao Zeng, Shenxin Pan, Youlu Yan, Dongmei Shen, Zhengrong Huang, Wenhai |
author_facet | Liang, Meihao Gu, Lili Zhang, Hongjie Min, Jingli Wang, Zunyuan Ma, Zhen Zhang, Chixiao Zeng, Shenxin Pan, Youlu Yan, Dongmei Shen, Zhengrong Huang, Wenhai |
author_sort | Liang, Meihao |
collection | PubMed |
description | [Image: see text] The abnormal phosphorylation of the τ-protein is a typical early pathological feature of Alzheimer’s disease (AD). The excessive phosphorylation of the τ-protein in the brain causes the formation of neurofibrillary tangles (NFTs) and increases the neurotoxicity of amyloid-β (Aβ). Thus, targeting the τ-protein is considered a promising strategy for treating AD. Herein, we designed and synthesized a series of molecules containing bifunctional groups to recognize the τ-protein and the E3 ligase. The molecules were examined in vitro, and their effects were tested on PC12 cells. In addition, we further studied the pharmacokinetics of compound I3 in healthy rats. Our data showed that compound I3 could effectively degrade τ-protein, reduce Aβ-induced cytotoxicity, and regulate the uneven distribution of mitochondria, which may open a new therapeutic strategy for the treatment of AD. |
format | Online Article Text |
id | pubmed-9352321 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-93523212022-08-05 Design, Synthesis, and Bioactivity of Novel Bifunctional Small Molecules for Alzheimer’s disease Liang, Meihao Gu, Lili Zhang, Hongjie Min, Jingli Wang, Zunyuan Ma, Zhen Zhang, Chixiao Zeng, Shenxin Pan, Youlu Yan, Dongmei Shen, Zhengrong Huang, Wenhai ACS Omega [Image: see text] The abnormal phosphorylation of the τ-protein is a typical early pathological feature of Alzheimer’s disease (AD). The excessive phosphorylation of the τ-protein in the brain causes the formation of neurofibrillary tangles (NFTs) and increases the neurotoxicity of amyloid-β (Aβ). Thus, targeting the τ-protein is considered a promising strategy for treating AD. Herein, we designed and synthesized a series of molecules containing bifunctional groups to recognize the τ-protein and the E3 ligase. The molecules were examined in vitro, and their effects were tested on PC12 cells. In addition, we further studied the pharmacokinetics of compound I3 in healthy rats. Our data showed that compound I3 could effectively degrade τ-protein, reduce Aβ-induced cytotoxicity, and regulate the uneven distribution of mitochondria, which may open a new therapeutic strategy for the treatment of AD. American Chemical Society 2022-07-20 /pmc/articles/PMC9352321/ /pubmed/35936449 http://dx.doi.org/10.1021/acsomega.2c02130 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Liang, Meihao Gu, Lili Zhang, Hongjie Min, Jingli Wang, Zunyuan Ma, Zhen Zhang, Chixiao Zeng, Shenxin Pan, Youlu Yan, Dongmei Shen, Zhengrong Huang, Wenhai Design, Synthesis, and Bioactivity of Novel Bifunctional Small Molecules for Alzheimer’s disease |
title | Design, Synthesis,
and Bioactivity of Novel Bifunctional
Small Molecules for Alzheimer’s disease |
title_full | Design, Synthesis,
and Bioactivity of Novel Bifunctional
Small Molecules for Alzheimer’s disease |
title_fullStr | Design, Synthesis,
and Bioactivity of Novel Bifunctional
Small Molecules for Alzheimer’s disease |
title_full_unstemmed | Design, Synthesis,
and Bioactivity of Novel Bifunctional
Small Molecules for Alzheimer’s disease |
title_short | Design, Synthesis,
and Bioactivity of Novel Bifunctional
Small Molecules for Alzheimer’s disease |
title_sort | design, synthesis,
and bioactivity of novel bifunctional
small molecules for alzheimer’s disease |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9352321/ https://www.ncbi.nlm.nih.gov/pubmed/35936449 http://dx.doi.org/10.1021/acsomega.2c02130 |
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