Antiviral strategies based on targeted protein degradation: an overview of the literature and future outlook

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-09-30 DOI:10.1016/j.ejmech.2025.118208

Fan Zhou, Dazhou Shi, Baohu Li, Mei Wang, Shujing Xu, Jinfei Yang, Xu Deng, Peng Zhan

引用次数: 0

Abstract

Viral infections persist as global threats, with traditional therapies limited by resistance and narrow targets. This review highlights targeted protein degradation (TPD) as a transformative antiviral strategy, covering proteolysis-targeting chimeras (PROTACs), hydrophobic tagging (HyT), and lysosome-targeting chimeras (LYTACs) against Influenza A virus (IAV), Human immunodeficiency virus (HIV), Hepatitis B virus (HBV), and Hepatitis C virus (HCV). TPD’s “event-driven” mechanism degrades “undruggable” viral/host proteins (e.g., PA, HDAC6) to bypass resistance. Key breakthroughs include PROTAC vaccines (10⁶-fold titer reduction) and liver-targeted degraders. It addresses pharmacokinetic/off-target challenges, proposing multi-target strategies and organ-specific delivery to redefine antiviral therapy from passive control to active eradication.

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基于靶向蛋白降解的抗病毒策略：文献综述和未来展望

病毒感染仍然是全球威胁，传统疗法受到耐药性和狭窄靶点的限制。这篇综述强调了靶向蛋白降解（TPD）作为一种革命性的抗病毒策略，包括靶向蛋白水解嵌合体（PROTACs）、疏水标记（HyT）和靶向溶酶体嵌合体（LYTACs）对抗甲型流感病毒（IAV）、人类免疫缺陷病毒（HIV）、乙型肝炎病毒（HBV）和丙型肝炎病毒（HCV）。TPD的“事件驱动”机制可降解“不可药物”的病毒/宿主蛋白（如PA、HDAC6）以绕过耐药性。关键的突破包括PROTAC疫苗（滴度降低106倍）和肝脏靶向降解物。它解决了药代动力学/脱靶挑战，提出了多靶点策略和器官特异性递送，重新定义了抗病毒治疗，从被动控制到主动根除。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.