Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's disease
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 che...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-04-01
|
| Series: | Acta Pharmaceutica Sinica B |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383519306549 |
| _version_ | 1819227509916434432 |
|---|---|
| author | Xiaokang Li Jian Lu Yixiang Xu Jiaying Wang Xiaoxia Qiu Lei Fan Baoli Li Wenwen Liu Fei Mao Jin Zhu Xu Shen Jian Li |
| author_facet | Xiaokang Li Jian Lu Yixiang Xu Jiaying Wang Xiaoxia Qiu Lei Fan Baoli Li Wenwen Liu Fei Mao Jin Zhu Xu Shen Jian Li |
| author_sort | Xiaokang Li |
| collection | DOAJ |
| description | 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. Key words: Alzheimer's disease, Autophagy, Nitazoxanide, β-amyloid, Tau protein |
| first_indexed | 2024-12-23T10:42:31Z |
| format | Article |
| id | doaj.art-cc3a5c2e4c81408fa01d9e7fac6f8f02 |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-12-23T10:42:31Z |
| publishDate | 2020-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-cc3a5c2e4c81408fa01d9e7fac6f8f022022-12-21T17:50:07ZengElsevierActa Pharmaceutica Sinica B2211-38352020-04-01104646666Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's diseaseXiaokang Li0Jian Lu1Yixiang Xu2Jiaying Wang3Xiaoxia Qiu4Lei Fan5Baoli Li6Wenwen Liu7Fei Mao8Jin Zhu9Xu Shen10Jian Li11State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, ChinaSchool of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaState Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, ChinaSchool of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaState Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, ChinaCenter for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, ChinaState Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, ChinaState Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, ChinaState Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, ChinaState Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, ChinaSchool of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing 210023, China; Corresponding authors. Tel./fax: +86 21 64252584.State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; Corresponding authors. Tel./fax: +86 21 64252584.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. Key words: Alzheimer's disease, Autophagy, Nitazoxanide, β-amyloid, Tau proteinhttp://www.sciencedirect.com/science/article/pii/S2211383519306549 |
| spellingShingle | Xiaokang Li Jian Lu Yixiang Xu Jiaying Wang Xiaoxia Qiu Lei Fan Baoli Li Wenwen Liu Fei Mao Jin Zhu Xu Shen Jian Li Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's disease Acta Pharmaceutica Sinica B |
| title | Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's disease |
| title_full | Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's disease |
| title_fullStr | Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's disease |
| title_full_unstemmed | Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's disease |
| title_short | Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's disease |
| title_sort | discovery of nitazoxanide based derivatives as autophagy activators for the treatment of alzheimer s disease |
| url | http://www.sciencedirect.com/science/article/pii/S2211383519306549 |
| work_keys_str_mv | AT xiaokangli discoveryofnitazoxanidebasedderivativesasautophagyactivatorsforthetreatmentofalzheimersdisease AT jianlu discoveryofnitazoxanidebasedderivativesasautophagyactivatorsforthetreatmentofalzheimersdisease AT yixiangxu discoveryofnitazoxanidebasedderivativesasautophagyactivatorsforthetreatmentofalzheimersdisease AT jiayingwang discoveryofnitazoxanidebasedderivativesasautophagyactivatorsforthetreatmentofalzheimersdisease AT xiaoxiaqiu discoveryofnitazoxanidebasedderivativesasautophagyactivatorsforthetreatmentofalzheimersdisease AT leifan discoveryofnitazoxanidebasedderivativesasautophagyactivatorsforthetreatmentofalzheimersdisease AT baolili discoveryofnitazoxanidebasedderivativesasautophagyactivatorsforthetreatmentofalzheimersdisease AT wenwenliu discoveryofnitazoxanidebasedderivativesasautophagyactivatorsforthetreatmentofalzheimersdisease AT feimao discoveryofnitazoxanidebasedderivativesasautophagyactivatorsforthetreatmentofalzheimersdisease AT jinzhu discoveryofnitazoxanidebasedderivativesasautophagyactivatorsforthetreatmentofalzheimersdisease AT xushen discoveryofnitazoxanidebasedderivativesasautophagyactivatorsforthetreatmentofalzheimersdisease AT jianli discoveryofnitazoxanidebasedderivativesasautophagyactivatorsforthetreatmentofalzheimersdisease |