Characterization and Noncovalent Inhibition of the Deubiquitinase and deISGylase Activity of SARS-CoV-2 Papain-Like Protease.,ACS Infectious Diseases

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Characterization and Noncovalent Inhibition of the Deubiquitinase and deISGylase Activity of SARS-CoV-2 Papain-Like Protease.
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2020-05-19 , DOI: 10.1021/acsinfecdis.0c00168
Brendan T Freitas ₁ , Ian A Durie ₁ , Jackelyn Murray ₂ , Jaron E Longo ₁ , Holden C Miller ₁ , David Crich _{1,

3} , Robert Jeff Hogan ₂ , Ralph A Tripp ₂ , Scott D Pegan ₁

Affiliation

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent for COVID-19, is a novel human betacoronavirus that is rapidly spreading worldwide. The outbreak currently includes over 3.7 million cases and 260,000 fatalities. As a betacoronavirus, SARS-CoV-2 encodes for a papain-like protease (PLpro) that is likely responsible for cleavage of the coronavirus (CoV) viral polypeptide. The PLpro is also responsible for suppression of host innate immune responses by virtue of its ability to reverse host ubiquitination and ISGylation events. Here, the biochemical activity of SARS-CoV-2 PLpro against ubiquitin (Ub) and interferon-stimulated gene product 15 (ISG15) substrates is evaluated, revealing that the protease has a marked reduction in its ability to process K48 linked Ub substrates compared to its counterpart in SARS-CoV. Additionally, its substrate activity more closely mirrors that of the PLpro from the Middle East respiratory syndrome coronavirus and prefers ISG15s from certain species including humans. Additionally, naphthalene based PLpro inhibitors are shown to be effective at halting SARS-CoV-2 PLpro activity as well as SARS-CoV-2 replication.

中文翻译：

SARS-CoV-2 木瓜蛋白酶样蛋白酶的去泛素酶和去ISG 酶活性的表征和非共价抑制。

严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 是 COVID-19 的病原体，是一种新型人类 β 冠状病毒，正在全球范围内迅速传播。目前，疫情已导致超过 370 万例病例和 26 万人死亡。作为一种 β 冠状病毒，SARS-CoV-2 编码一种木瓜蛋白酶样蛋白酶 (PLpro)，该蛋白酶可能负责切割冠状病毒 (CoV) 病毒多肽。PLpro 还凭借其逆转宿主泛素化和 ISGylation 事件的能力，负责抑制宿主先天免疫反应。在此，评估了 SARS-CoV-2 PLpro 针对泛素 (Ub) 和干扰素刺激的基因产物 15 (ISG15) 底物的生化活性，结果表明，与普通蛋白酶相比，该蛋白酶处理 K48 连接的 Ub 底物的能力显着降低。 SARS-CoV 中的对应物。此外，其底物活性更接近中东呼吸综合征冠状病毒的 PLpro，并且更喜欢来自某些物种（包括人类）的 ISG15。此外，基于萘的 PLpro 抑制剂被证明可以有效阻止 SARS-CoV-2 PLpro 活性以及 SARS-CoV-2 复制。

更新日期：2020-05-19

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