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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...

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Autores principales: Liang, Meihao, Gu, Lili, Zhang, Hongjie, Min, Jingli, Wang, Zunyuan, Ma, Zhen, Zhang, Chixiao, Zeng, Shenxin, Pan, Youlu, Yan, Dongmei, Shen, Zhengrong, Huang, Wenhai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
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.
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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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