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利用 PROTAC 技术对抗 H5N1 流感:病毒破坏的新前沿。

Harnessing PROTACs to combat H5N1 influenza: A new frontier in viral destruction.

机构信息

Center for Global Health Research, Saveetha Institute of Medical and Technical Sciences, Saveetha Medical College and Hospital, Chennai, India.

Department of Microbiology, Adamas University, Kolkata, India.

出版信息

J Med Virol. 2024 Sep;96(9):e29926. doi: 10.1002/jmv.29926.

Abstract

H5N1, a highly pathogenic avian influenza virus, poses an ongoing and significant threat to global public health, primarily due to its potential to cause severe respiratory illness and high mortality rates in humans. Despite extensive efforts in vaccination and antiviral therapy, H5N1 continues to exhibit high mutation rates, resulting in recurrent outbreaks and the emergence of drug-resistant strains. Traditional antiviral therapies, such as neuraminidase inhibitors and M2 ion channel blockers, have demonstrated limited efficacy, necessitating the exploration of innovative therapeutic strategies. Proteolysis-targeting chimeras (PROTACs) emerge as a novel and promising approach, leveraging the ubiquitin-proteasome system to selectively degrade pathogenic proteins. Unlike conventional inhibitors that only block protein function, PROTACs eliminate the target protein, providing a sustained therapeutic effect and potentially reducing the development of resistance. This paper offers a comprehensive examination of the current landscape of H5N1 infections, detailing the pathogenesis and challenges associated with existing treatments. It further explores the mechanism of action, design, and therapeutic potential of PROTACs in inhibiting H5N1. By targeting essential viral proteins, such as hemagglutinin and the RNA-dependent RNA polymerase complex, PROTACs hold the potential to revolutionize the treatment of H5N1 infections, offering a new frontier in antiviral therapy.

摘要

H5N1 是一种高致病性禽流感病毒,对全球公共卫生构成持续且重大的威胁,主要是因为它有可能导致人类严重的呼吸道疾病和高死亡率。尽管在疫苗接种和抗病毒治疗方面进行了广泛的努力,但 H5N1 仍继续表现出高突变率,导致反复爆发和耐药株的出现。传统的抗病毒疗法,如神经氨酸酶抑制剂和 M2 离子通道阻滞剂,已证明疗效有限,因此需要探索创新的治疗策略。蛋白水解靶向嵌合体(PROTACs)作为一种新颖而有前途的方法出现,利用泛素-蛋白酶体系统选择性地降解致病蛋白。与仅阻断蛋白功能的传统抑制剂不同,PROTACs 可消除靶蛋白,提供持续的治疗效果,并可能降低耐药性的发展。本文全面考察了 H5N1 感染的现状,详细描述了与现有治疗方法相关的发病机制和挑战。它进一步探讨了 PROTACs 抑制 H5N1 的作用机制、设计和治疗潜力。通过靶向血凝素和 RNA 依赖性 RNA 聚合酶复合物等关键病毒蛋白,PROTACs 有可能彻底改变 H5N1 感染的治疗方法,为抗病毒治疗开辟新的前沿。

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