Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's disease
© 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V..
Drug repurposing is an efficient strategy for new drug discovery. Our latest study found that nitazoxanide (NTZ), an approved anti-parasite drug, was an autophagy activator and could alleviate the symptom of Alzheimer's disease (AD). In order to further improve the efficacy and discover new chemical entities, a series of NTZ-based derivatives were designed, synthesized, and evaluated as autophagy activator against AD. All compounds were screened by the inhibition of phosphorylation of p70S6K, which was the direct substrate of mammalian target of rapamycin (mTOR) and its phosphorylation level could reflect the mTOR-dependent autophagy level. Among these analogs, compound 22 exhibited excellent potency in promoting β-amyloid (Aβ) clearance, inhibiting tau phosphorylation, as well as stimulating autophagy both in vitro and in vivo. What's more, 22 could effectively improve the memory and cognitive impairments in APP/PS1 transgenic AD model mice. These results demonstrated that 22 was a potential candidate for the treatment of AD.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:10 |
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| Enthalten in: |
Acta pharmaceutica Sinica. B - 10(2020), 4 vom: 16. Apr., Seite 646-666 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Li, Xiaokang [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Revised 28.09.2020 published: Print-Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1016/j.apsb.2019.07.006 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM309068568 |
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| 100 | 1 | |a Li, Xiaokang |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's disease |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
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| 500 | |a Date Revised 28.09.2020 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. | ||
| 520 | |a Drug repurposing is an efficient strategy for new drug discovery. Our latest study found that nitazoxanide (NTZ), an approved anti-parasite drug, was an autophagy activator and could alleviate the symptom of Alzheimer's disease (AD). In order to further improve the efficacy and discover new chemical entities, a series of NTZ-based derivatives were designed, synthesized, and evaluated as autophagy activator against AD. All compounds were screened by the inhibition of phosphorylation of p70S6K, which was the direct substrate of mammalian target of rapamycin (mTOR) and its phosphorylation level could reflect the mTOR-dependent autophagy level. Among these analogs, compound 22 exhibited excellent potency in promoting β-amyloid (Aβ) clearance, inhibiting tau phosphorylation, as well as stimulating autophagy both in vitro and in vivo. What's more, 22 could effectively improve the memory and cognitive impairments in APP/PS1 transgenic AD model mice. These results demonstrated that 22 was a potential candidate for the treatment of AD | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a AChEIs, acetylcholinesterase inhibitors | |
| 650 | 4 | |a AD, Alzheimer's disease | |
| 650 | 4 | |a APP, amyloid precursor protein | |
| 650 | 4 | |a Alzheimer's disease | |
| 650 | 4 | |a Autophagy | |
| 650 | 4 | |a Aβ, β-amyloid | |
| 650 | 4 | |a BBB, blood–brain barrier | |
| 650 | 4 | |a CNS, central nervous system | |
| 650 | 4 | |a MWM, Morris Water Maze | |
| 650 | 4 | |a NCEs, new chemical entities | |
| 650 | 4 | |a NFTs, neurofibrillary tangles | |
| 650 | 4 | |a NMDA, N-methyl-d-aspartate | |
| 650 | 4 | |a NTZ, nitazoxanide | |
| 650 | 4 | |a Nitazoxanide | |
| 650 | 4 | |a PAMPA, parallel artificial membrane permeation assay | |
| 650 | 4 | |a PBL, porcine brain lipid | |
| 650 | 4 | |a SPs, senile plaques | |
| 650 | 4 | |a Tau protein | |
| 650 | 4 | |a WORT, wortmannin | |
| 650 | 4 | |a mTOR, mammalian target of rapamycin | |
| 650 | 4 | |a β-amyloid | |
| 700 | 1 | |a Lu, Jian |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Yixiang |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jiaying |e verfasserin |4 aut | |
| 700 | 1 | |a Qiu, Xiaoxia |e verfasserin |4 aut | |
| 700 | 1 | |a Fan, Lei |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Baoli |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Wenwen |e verfasserin |4 aut | |
| 700 | 1 | |a Mao, Fei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Jin |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Xu |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Jian |e verfasserin |4 aut | |
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