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病毒利用 YxxØ 基序与宿主 AP2M1 相互作用进行复制：一个易受攻击的广谱抗病毒靶点。

Viruses harness YxxØ motif to interact with host AP2M1 for replication: A vulnerable broad-spectrum antiviral target.

机构信息

State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.

Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.

出版信息

Sci Adv. 2020 Aug 28;6(35):eaba7910. doi: 10.1126/sciadv.aba7910. eCollection 2020 Aug.

DOI:10.1126/sciadv.aba7910
PMID:32923629
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7455044/
Abstract

Targeting a universal host protein exploited by most viruses would be a game-changing strategy that offers broad-spectrum solution and rapid pandemic control including the current COVID-19. Here, we found a common YxxØ-motif of multiple viruses that exploits host AP2M1 for intracellular trafficking. A library chemical, -(p-amylcinnamoyl)anthranilic acid (ACA), was identified to interrupt AP2M1-virus interaction and exhibit potent antiviral efficacy against a number of viruses in vitro and in vivo, including the influenza A viruses (IAVs), Zika virus (ZIKV), human immunodeficiency virus, and coronaviruses including MERS-CoV and SARS-CoV-2. YxxØ mutation, AP2M1 depletion, or disruption by ACA causes incorrect localization of viral proteins, which is exemplified by the failure of nuclear import of IAV nucleoprotein and diminished endoplasmic reticulum localization of ZIKV-NS3 and enterovirus-A71-2C proteins, thereby suppressing viral replication. Our study reveals an evolutionarily conserved mechanism of protein-protein interaction between host and virus that can serve as a broad-spectrum antiviral target.

摘要

针对大多数病毒利用的通用宿主蛋白将是一种改变游戏规则的策略，可提供广谱解决方案和快速控制大流行，包括当前的 COVID-19。在这里，我们发现了多种病毒的共同 YxxØ 基序，该基序利用宿主 AP2M1 进行细胞内运输。一种文库化学物质，-(对戊基肉桂酰)邻氨基苯甲酸（ACA），被鉴定为可中断 AP2M1-病毒相互作用，并在体外和体内表现出针对多种病毒的强大抗病毒功效，包括甲型流感病毒（IAV）、寨卡病毒（ZIKV）、人类免疫缺陷病毒和冠状病毒，包括 MERS-CoV 和 SARS-CoV-2。YxxØ 突变、AP2M1 耗竭或 ACA 破坏会导致病毒蛋白定位不正确，这表现在 IAV 核蛋白的核输入失败和 ZIKV-NS3 和肠病毒-A71-2C 蛋白的内质网定位减少，从而抑制病毒复制。我们的研究揭示了宿主和病毒之间的一种进化保守的蛋白质-蛋白质相互作用机制，可作为广谱抗病毒靶标。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d003/7455044/1c6377777a7d/aba7910-F6.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d003/7455044/82a2519c046a/aba7910-F4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d003/7455044/88e552873030/aba7910-F5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d003/7455044/1c6377777a7d/aba7910-F6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d003/7455044/fcdb6fb2cb41/aba7910-F1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d003/7455044/af6ecb6b119a/aba7910-F2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d003/7455044/a822099ca9e0/aba7910-F3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d003/7455044/82a2519c046a/aba7910-F4.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d003/7455044/1c6377777a7d/aba7910-F6.jpg

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