AI-driven discovery of brain-penetrant Galectin-3 inhibitors for Alzheimer's disease therapy
Galectin-3 (Gal-3) has emerged as a critical regulator of neuroinflammation and a promising therapeutic target for Alzheimer's disease (AD). Nevertheless, the development of brain-penetrant small-molecule Gal-3 inhibitors poses a significant challenge. To address this, we employed an artificial...
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| Language: | English |
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Elsevier
2025-08-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661825002592 |
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| author | Xueyan Liu Jiexin Xu Shuping Zheng Yaoyao Yang Yuchong Xie Jinyu Liu Jian Zhong Huiyao Zhang Jiajing Chen Chaoxian Dai Dingyan Wang Jiewei Luo Xiaochun Chen Feisheng Zhong Zu-Cheng Ye |
| author_facet | Xueyan Liu Jiexin Xu Shuping Zheng Yaoyao Yang Yuchong Xie Jinyu Liu Jian Zhong Huiyao Zhang Jiajing Chen Chaoxian Dai Dingyan Wang Jiewei Luo Xiaochun Chen Feisheng Zhong Zu-Cheng Ye |
| author_sort | Xueyan Liu |
| collection | DOAJ |
| description | Galectin-3 (Gal-3) has emerged as a critical regulator of neuroinflammation and a promising therapeutic target for Alzheimer's disease (AD). Nevertheless, the development of brain-penetrant small-molecule Gal-3 inhibitors poses a significant challenge. To address this, we employed an artificial intelligence (AI)-driven drug discovery platform, identifying FJMU1887 as a novel Gal-3 inhibitor possessing optimized pharmacokinetic properties and favorable blood-brain barrier (BBB) permeability. Following AI-based virtual screening and structure prioritization, FJMU1887 demonstrated direct binding to Gal-3 with an affinity (Kd) of 1.55 μM, determined by microscale thermophoresis (MST). Crucially, mechanistic studies revealed that FJMU1887 disrupts the Gal-3–TREM2 interaction, as evidenced by fluorescence resonance energy transfer (FRET) and fluorescence correlation spectroscopy (FCS) assays. In vitro, FJMU1887 suppressed inflammatory responses in BV-2 microglial cells, inhibiting TNF-α with an IC₅₀ of 2.36 ± 0.37 μM, without inducing cytotoxicity. Pharmacokinetic assessments via parallel artificial membrane permeability assay for BBB (PAMPA-BBB) and in situ brain perfusion revealed effective blood-brain barrier penetration by FJMU1887, though partial P-glycoprotein-mediated efflux was observed. In vivo, 30-day oral administration of FJMU1887 to 14-month-old 5 ×FAD mice significantly reduced Gal-3 expression, attenuated microglial activation and neuroinflammation, decreased amyloid-β burden, and restored synaptic integrity. Notably, FJMU1887 improved cognitive performance in both 5 ×FAD and oligomeric Aβ-induced cognitive impairment mouse models across multiple behavioral paradigms. Collectively, FJMU1887 represents a brain-penetrant small-molecule Gal-3 inhibitor with dual anti-neuroinflammatory and cognition-enhancing effects, establishing it as a promising lead compound for AD therapy. |
| format | Article |
| id | doaj-art-53c7ccddce4248138cab7c339e908161 |
| institution | DOAJ |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-53c7ccddce4248138cab7c339e9081612025-08-20T02:45:42ZengElsevierPharmacological Research1096-11862025-08-0121810783410.1016/j.phrs.2025.107834AI-driven discovery of brain-penetrant Galectin-3 inhibitors for Alzheimer's disease therapyXueyan Liu0Jiexin Xu1Shuping Zheng2Yaoyao Yang3Yuchong Xie4Jinyu Liu5Jian Zhong6Huiyao Zhang7Jiajing Chen8Chaoxian Dai9Dingyan Wang10Jiewei Luo11Xiaochun Chen12Feisheng Zhong13Zu-Cheng Ye14School of Pharmacy, Fujian Medical University, Fuzhou, China; Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Drug Target Discovery and Structural and Functional Research, School of Pharmacy, Fujian Medical University, Fuzhou, ChinaSchool of Pharmacy, Fujian Medical University, Fuzhou, ChinaPublic Technology Service Center, Fujian Medical University, Fuzhou, ChinaFujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, ChinaFujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, ChinaFujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, ChinaFujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, ChinaFujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, ChinaFujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, ChinaFujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, ChinaLingang Laboratory, Shanghai, ChinaDepartment of Traditional Chinese Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, ChinaDepartment of Neurology, Fujian Medical University Union Hospital, Fujian Key Laboratory of Molecular Neurology and Institute of Neuroscience, Fujian Medical University, Fuzhou, China; Corresponding author.School of Pharmacy, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Drug Target Discovery and Structural and Functional Research, School of Pharmacy, Fujian Medical University, Fuzhou, China; Corresponding author at: School of Pharmacy, Fujian Medical University, Fuzhou, China.Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Corresponding author.Galectin-3 (Gal-3) has emerged as a critical regulator of neuroinflammation and a promising therapeutic target for Alzheimer's disease (AD). Nevertheless, the development of brain-penetrant small-molecule Gal-3 inhibitors poses a significant challenge. To address this, we employed an artificial intelligence (AI)-driven drug discovery platform, identifying FJMU1887 as a novel Gal-3 inhibitor possessing optimized pharmacokinetic properties and favorable blood-brain barrier (BBB) permeability. Following AI-based virtual screening and structure prioritization, FJMU1887 demonstrated direct binding to Gal-3 with an affinity (Kd) of 1.55 μM, determined by microscale thermophoresis (MST). Crucially, mechanistic studies revealed that FJMU1887 disrupts the Gal-3–TREM2 interaction, as evidenced by fluorescence resonance energy transfer (FRET) and fluorescence correlation spectroscopy (FCS) assays. In vitro, FJMU1887 suppressed inflammatory responses in BV-2 microglial cells, inhibiting TNF-α with an IC₅₀ of 2.36 ± 0.37 μM, without inducing cytotoxicity. Pharmacokinetic assessments via parallel artificial membrane permeability assay for BBB (PAMPA-BBB) and in situ brain perfusion revealed effective blood-brain barrier penetration by FJMU1887, though partial P-glycoprotein-mediated efflux was observed. In vivo, 30-day oral administration of FJMU1887 to 14-month-old 5 ×FAD mice significantly reduced Gal-3 expression, attenuated microglial activation and neuroinflammation, decreased amyloid-β burden, and restored synaptic integrity. Notably, FJMU1887 improved cognitive performance in both 5 ×FAD and oligomeric Aβ-induced cognitive impairment mouse models across multiple behavioral paradigms. Collectively, FJMU1887 represents a brain-penetrant small-molecule Gal-3 inhibitor with dual anti-neuroinflammatory and cognition-enhancing effects, establishing it as a promising lead compound for AD therapy.http://www.sciencedirect.com/science/article/pii/S1043661825002592Galectin-3Cognitive functionAlzheimer's diseaseNeuroinflammationMicroglial activation |
| spellingShingle | Xueyan Liu Jiexin Xu Shuping Zheng Yaoyao Yang Yuchong Xie Jinyu Liu Jian Zhong Huiyao Zhang Jiajing Chen Chaoxian Dai Dingyan Wang Jiewei Luo Xiaochun Chen Feisheng Zhong Zu-Cheng Ye AI-driven discovery of brain-penetrant Galectin-3 inhibitors for Alzheimer's disease therapy Pharmacological Research Galectin-3 Cognitive function Alzheimer's disease Neuroinflammation Microglial activation |
| title | AI-driven discovery of brain-penetrant Galectin-3 inhibitors for Alzheimer's disease therapy |
| title_full | AI-driven discovery of brain-penetrant Galectin-3 inhibitors for Alzheimer's disease therapy |
| title_fullStr | AI-driven discovery of brain-penetrant Galectin-3 inhibitors for Alzheimer's disease therapy |
| title_full_unstemmed | AI-driven discovery of brain-penetrant Galectin-3 inhibitors for Alzheimer's disease therapy |
| title_short | AI-driven discovery of brain-penetrant Galectin-3 inhibitors for Alzheimer's disease therapy |
| title_sort | ai driven discovery of brain penetrant galectin 3 inhibitors for alzheimer s disease therapy |
| topic | Galectin-3 Cognitive function Alzheimer's disease Neuroinflammation Microglial activation |
| url | http://www.sciencedirect.com/science/article/pii/S1043661825002592 |
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