基于片段的 SARS-CoV-2 Papain 样蛋白酶（PLpro）筛选

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-07-23 DOI:10.1021/acsmedchemlett.4c00238

Ashley J. Taylor, Kangsa Amporndanai, Tyson A. Rietz, Bin Zhao, Anusha Thiruvaipati, Qiangqiang Wei, Taylor M. South, Mackenzie M. Crow, Chideraa Apakama, John L. Sensintaffar, Jason Phan, Taekyu Lee, Stephen W. Fesik

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引用次数: 0

摘要

由于冠状病毒的传播率很高，在过去二十年里，冠状病毒曾多次导致病毒爆发。最致命的疫情是最近的 Covid-19 大流行，造成全球 700 多万人死亡。SARS-CoV-2 木瓜蛋白酶（PLPro）在病毒复制和宿主免疫抑制中起着关键作用，在冠状病毒家族中高度保守，因此是理想的药物靶点。在本文中，我们介绍了利用蛋白质观测核磁共振实验对 PLPro 进行的片段筛选，确定了 77 个命中片段。对核磁共振扰动模式和 X 射线共晶体结构的分析表明，片段与蛋白质的两个不同区域结合。重要的是，所发现的片段没有一个与已报道的少数抑制剂属于同一化学类别，从而发现了一类新型的 PLPro 抑制剂。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Fragment-Based Screen of SARS-CoV-2 Papain-like Protease (PLpro)

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Fragment-Based Screen of SARS-CoV-2 Papain-like Protease (PLpro)

Coronaviruses have been responsible for numerous viral outbreaks in the past two decades due to the high transmission rate of this family of viruses. The deadliest outbreak is the recent Covid-19 pandemic, which resulted in over 7 million deaths worldwide. SARS-CoV-2 papain-like protease (PL^Pro) plays a key role in both viral replication and host immune suppression and is highly conserved across the coronavirus family, making it an ideal drug target. Herein we describe a fragment-based screen against PL^Pro using protein-observed NMR experiments, identifying 77 hit fragments. Analyses of NMR perturbation patterns and X-ray cocrystallized structures reveal fragments bind to two distinct regions of the protein. Importantly none of the fragments identified belong to the same chemical class as the few reported inhibitors, allowing for the discovery of a novel class of PL^Pro inhibitors.

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.