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利用多重化蛋白解向金马进行全面的A型流感病毒向

Yang-Yang Liu¹, Cong Yu¹, Jing Li²

¹State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Centre for New Organic Matter, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, School of Medicine, and Frontiers Science Centre for Cell Responses, Nankai University, Tianjin 300071, P. R. China.

Journal of the American Chemical Society

|November 3, 2025

概括

一种新的蛋白质分解向金马 (PROTAC) 策略同时降解多个流感A病毒 (IAV) 组件. 这种多目标方法提供了强大的,广泛的抗病毒活性,并克服了耐药性,从而推进了流感治疗方法.

科学领域:

病毒学
分子生物学
药物发现

背景情况:

由于快速突变和免疫规避,A型流感病毒 (IAV) 对全球健康构成重大风险.
现有的抗病毒疗法受限于单一向机制和药物耐药性的出现.

研究的目的:

开发一种新型的多重化蛋白解-向化体 (PROTAC) 策略,用于同时降解多个病毒点.
通过创建抗药性治疗来解决目前流感治疗的局限性.

主要方法:

设计了一个 PROTAC 分子,集成一个聚核酸连接体,以 E3 连接酶招募器为目标.
该药物向并降解病毒核糖蛋白 (vRNP) 复合体的多个组成部分,包括NP和聚合酶子单元 (PB1,PB2,PA).
在体外和体内评估抗病毒功效,效果持续时间和耐药性.

主要成果:

该策略有效降解了多个vRNP组件,破坏了病毒复制.
PROTAC2表现出强大的抗病毒活性 (0. 8μM),持续抑制 (> 48小时),表现优于利巴维林.
通过多目标方法,发现了抗药性高基因障碍,并显示了对IAV菌株的广泛活性.

结论:

针对vRNP复合体的多重复合PROTAC提供了对流感A病毒的高度有效和持久的治疗策略.
这种方法克服了当前抗病毒药物的局限性,为耐药候选药物提供了延长的治疗窗口.
这种创新疗法通过解决突变,免疫规避和抗药性等关键挑战, 推动了流感治疗.

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