Characterization and noncovalent inhibition of the K63-deubiquitinase activity of SARS-cov-2 PLpro

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY Antiviral research Pub Date : 2024-06-22 DOI:10.1016/j.antiviral.2024.105944

Xin Liu , Miao Zheng , Hongqing Zhang , Bo Feng , Jiaqi Li , Yanan Zhang , Ji Zhang , Na Zhao , Chaoqiang Li , Ning Song , Bin Song , Dongyuan Yang , Jin Chen , Ao Qi , Linxiang Zhao , Cheng Luo , Yi Zang , Hong Liu , Jia Li , Bo Zhang , Jie Zheng

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引用次数: 0

Abstract

SARS-CoV-2 papain-like protease (PLpro) could facilitate viral replication and host immune evasion by respectively hydrolyzing viral polyprotein and host ubiquitin conjugates, thereby rendering itself as an important antiviral target. Yet few noncovalent PLpro inhibitors of SARS-CoV-2 have been reported with improved directed towards pathogenic deubiquitinating activities inhibition. Herein, we report that coronavirus PLpro proteases have distinctive substrate bias and are conserved to deubiquitylate K63-linked polyubiquitination, thereby attenuating host type I interferon response. We identify a noncovalent compound specifically optimized towards halting the K63-deubiquitinase activity of SARS-CoV-2 PLpro, but not other coronavirus (CoV) counterparts or host deubiquitinase. Contrasting with GRL-0617, a SARS-CoV-1 PLpro inhibitor, SIMM-036 is 50-fold and 7-fold (half maximal inhibitory concentration (IC₅₀)) more potent to inhibit viral replication during SARS-CoV-2 infection and restore the host interferon-β (IFN-β) response in human angiotensin-converting enzyme 2 (hACE2)-HeLa cells, respectively. Structure-activity relationship (SAR) analysis further reveals the importance of BL2 groove of PLpro, which could determine the selectivity of K63-deubiquitinase activity of the enzyme.

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SARS-CoV-2 PLpro 的 K63-去泛素酶活性的特征和非共价抑制。

SARS-CoV-2 木瓜蛋白酶（PLpro）可通过分别水解病毒多聚蛋白和宿主泛素共轭物来促进病毒复制和宿主免疫逃避，从而使自身成为重要的抗病毒靶标。然而，针对抑制致病性去泛素化活性的 SARS-CoV-2 非共价 PLpro 抑制剂鲜有报道。在此，我们报告了冠状病毒 PLpro 蛋白酶具有独特的底物偏向性，并且在去泛素化 K63 链接的多泛素化方面是保守的，从而减弱了宿主的 I 型干扰素反应。我们发现了一种非共价化合物，这种化合物专门用于抑制 SARS-CoV-2 PLpro 的 K63-去泛素化酶活性，而不能抑制其他冠状病毒（CoV）对应物或宿主去泛素化酶的活性。与SARS-CoV-1 PLpro抑制剂GRL-0617相比，SIMM-036在抑制SARS-CoV-2感染过程中的病毒复制以及恢复宿主干扰素-β（IFN-β）在人血管紧张素转换酶2（hACE2）-HeLa细胞中的反应方面的效力分别提高了50倍和7倍（半最大抑制浓度（IC50））。结构-活性关系（SAR）分析进一步揭示了 PLpro 的 BL2 沟槽的重要性，它可以决定该酶的 K63-泛素化酶活性的选择性。

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来源期刊

Antiviral research 医学-病毒学

CiteScore

17.10

自引率

3.90%

发文量

157

审稿时长

34 days

期刊介绍： Antiviral Research is a journal that focuses on various aspects of controlling viral infections in both humans and animals. It is a platform for publishing research reports, short communications, review articles, and commentaries. The journal covers a wide range of topics including antiviral drugs, antibodies, and host-response modifiers. These topics encompass their synthesis, in vitro and in vivo testing, as well as mechanisms of action. Additionally, the journal also publishes studies on the development of new or improved vaccines against viral infections in humans. It delves into assessing the safety of drugs and vaccines, tracking the evolution of drug or vaccine-resistant viruses, and developing effective countermeasures. Another area of interest includes the identification and validation of new drug targets. The journal further explores laboratory animal models of viral diseases, investigates the pathogenesis of viral diseases, and examines the mechanisms by which viruses avoid host immune responses.