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Small-molecule LRRK2 inhibitors for PD therapy: Current achievements and future perspectives

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机构： [1]Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China [2]Department of Respiratory and Critical Care Medicine, Institute of Respiratory Health, Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China [3]Chengdu Fifth People’s Hospital, Chengdu, 611130, Sichuan, China [4]State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China [5]Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin, 150081, China

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Leucine-rich repeat kinase 2 (LRRK2) is a multifunctional protein that orchestrates a diverse array of cellular processes, including vesicle transport, autophagy, lysosome degradation, neurotransmission, and mitochondrial activity. Hyperactivation of LRRK2 triggers vesicle transport dysfunction, neuroinflammation, accumulation of α-synuclein, mitochondrial dysfunction, and the loss of cilia, ultimately leading to Parkinson's disease (PD). Therefore, targeting LRRK2 protein is a promising therapeutic strategy for PD. The clinical translation of LRRK2 inhibitors was historically impeded by issues surrounding tissue specificity. Recent studies have identified LRRK2 inhibitors that have no effect on peripheral tissues. Currently, there are four small-molecule LRRK2 inhibitors undergoing clinical trials. This review provides a summary of the structure and biological functions of LRRK2, along with an overview of the binding modes and structure-activity relationships (SARs) of small-molecule inhibitors targeting LRRK2. It offers valuable references for developing novel drugs targeting LRRK2.Copyright © 2023. Published by Elsevier Masson SAS.

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出版当年[2023]版：

大类 | 2 区

医学

小类 | 1 区药物化学

最新[2023]版：

大类 | 2 区

医学

小类 | 1 区药物化学

第一作者：

第一作者机构： [1]Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China

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通讯作者：

通讯机构： [1]Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China [2]Department of Respiratory and Critical Care Medicine, Institute of Respiratory Health, Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China [*1]Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China.

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