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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; Fujian Key Laboratory of Drug Target Discovery and Structural and Functional Research, School of Pharmacy, Fujian Medical University, Fuzhou, China.
School of Pharmacy, Fujian Medical University, Fuzhou, China.
Pharmacol Res. 2025 Aug;218:107834. doi: 10.1016/j.phrs.2025.107834. Epub 2025 Jun 19.
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.
半乳糖凝集素-3（Gal-3）已成为神经炎症的关键调节因子，也是治疗阿尔茨海默病（AD）的一个有前景的治疗靶点。然而，开发能够穿透血脑屏障的小分子Gal-3抑制剂面临重大挑战。为解决这一问题，我们采用了人工智能（AI）驱动的药物发现平台，确定FJMU1887是一种新型Gal-3抑制剂，具有优化的药代动力学特性和良好的血脑屏障（BBB）通透性。经过基于AI的虚拟筛选和结构优先级排序，通过微量热泳（MST）测定，FJMU1887与Gal-3直接结合，亲和力（Kd）为1.55 μM。至关重要的是，机制研究表明，FJMU1887破坏了Gal-3与触发受体表达的髓系细胞2（TREM2）的相互作用，荧光共振能量转移（FRET）和荧光相关光谱（FCS）分析证明了这一点。在体外，FJMU1887抑制BV-2小胶质细胞中的炎症反应，抑制肿瘤坏死因子-α（TNF-α）的IC₅₀为2.36±0.37 μM，且不诱导细胞毒性。通过血脑屏障平行人工膜通透性测定（PAMPA-BBB）和原位脑灌注进行的药代动力学评估表明，FJMU1887能有效穿透血脑屏障，不过观察到部分由P-糖蛋白介导的外排现象。在体内，对14月龄的5×FAD小鼠口服FJMU1887 30天，可显著降低Gal-3表达，减轻小胶质细胞激活和神经炎症，减少淀粉样β蛋白负担，并恢复突触完整性。值得注意的是，在多种行为范式中，FJMU1887改善了5×FAD和寡聚Aβ诱导的认知障碍小鼠模型的认知表现。总体而言，FJMU1887是一种能够穿透血脑屏障的小分子Gal-3抑制剂，具有双重抗神经炎症和增强认知的作用，使其成为AD治疗中一种有前景的先导化合物。
