School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China; Laboratory Animal Center, Nanjing University of Chinese Medicine, Nanjing, China.
School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
Biomed Pharmacother. 2023 Dec;168:115648. doi: 10.1016/j.biopha.2023.115648. Epub 2023 Oct 7.
Vimentin, an intermediate filament protein, crucially contributes to the pathogenesis of inflammatory bowel disease (IBD) by interacting with genetic risk factors, facilitating pathogen infection, and modulating both innate and adaptive immune responses. This study aimed to demonstrate preclinical proof-of-concept for targeting vimentin therapeutically in IBD across diverse etiologies.
The small molecule compound ALD-R491 was assessed for vimentin binding using microscale thermophoresis, off-target effects via Eurofins screening, and therapeutic effects in mice with dextran sulfate sodium (DSS)-induced acute colitis and in IL-10 KO with spontaneous colitis. Parameters measured included body weight, survival, disease activity, colon length, and histology. The study analyzed intestinal proinflammatory cytokines, Th17/Treg cells, and epithelial barrier molecules, along with gut microbiota profiling.
ALD-R491 specifically bound vimentin with a dissociation constant (KD) of 328 ± 12.66 nM and no off-target effects. In the DSS model, orally administered ALD-R491 exhibited dose-dependent therapeutic effects, superior to 5-ASA and Tofacitinib. In the IL-10 KO model, ALD-R491 significantly delayed colitis onset and progression, with near-zero disease activity index scores over a 15-week treatment. ALD-R491 consistently showed in both models a reduced proinflammatory cytokine expression, including TNF-α, IL-1β, IL-6, IL-17, IL-22, a rebalanced Th17/Treg axis by reducing RORγt while enhancing FoxP3 expression, and an improved epithelial barrier integrity by increasing intestinal expressions of Mucin-2, ZO-1 and Claudin5. The intestinal dysbiosis was restored with enriched presence of probiotics.
Targeting vimentin exhibits significant therapeutic effects on various facets of IBD pathogenesis, representing a compelling approach for the development of highly effective treatments in IBD.
中间丝蛋白波形蛋白通过与遗传风险因素相互作用、促进病原体感染以及调节先天和适应性免疫反应，在炎症性肠病（IBD）的发病机制中起着至关重要的作用。本研究旨在证明针对不同病因的 IBD 进行靶向波形蛋白治疗的临床前概念验证。
使用微量热泳动评估小分子化合物 ALD-R491 与波形蛋白的结合，通过 Eurofins 筛选评估其非靶点效应，并在葡聚糖硫酸钠（DSS）诱导的急性结肠炎小鼠和自发性结肠炎的 IL-10 KO 小鼠中评估其治疗效果。测量的参数包括体重、存活率、疾病活动度、结肠长度和组织学。该研究分析了肠道促炎细胞因子、Th17/Treg 细胞和上皮屏障分子，以及肠道微生物组谱。
ALD-R491 特异性结合波形蛋白，解离常数（KD）为 328±12.66 nM，无非靶点效应。在 DSS 模型中，口服给予 ALD-R491 表现出剂量依赖性的治疗效果，优于 5-ASA 和 Tofacitinib。在 IL-10 KO 模型中，ALD-R491 显著延迟结肠炎的发作和进展，在 15 周的治疗过程中，疾病活动指数评分接近零。在这两种模型中，ALD-R491 均表现出一致的降低促炎细胞因子表达，包括 TNF-α、IL-1β、IL-6、IL-17、IL-22，通过降低 RORγt 同时增强 FoxP3 表达来重新平衡 Th17/Treg 轴，以及通过增加肠道 Mucin-2、ZO-1 和 Claudin5 的表达来改善上皮屏障完整性。肠道菌群失调通过富集益生菌得到恢复。
靶向波形蛋白在 IBD 发病机制的各个方面均显示出显著的治疗效果，为开发 IBD 的高效治疗方法提供了一种有吸引力的方法。
