Discovery of broad-spectrum antivirals targeting viral proteases using in silico structural modeling and cellular analysis

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research Pub Date : 2025-07-29 DOI:10.1016/j.antiviral.2025.106245

Dharmeshkumar Patel , Ramyani De , Niloufar Azadi , Sujin Lee , Savannah Shooter , Sarah Amichai , Shaoman Zhou , Danielle Monroe , Cameron Mahanke , Tamara R. McBrayer , Michael Muczynski , Abdullah Al-Homoudi , Joseph Engel , Yury A. Bochkov , James E. Gern , Ladislau C. Kovari , Franck Amblard , Raymond F. Schinazi

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引用次数: 0

Abstract

The development of broad-spectrum antivirals is a high-priority goal to prevent future global outbreaks. Some antiviral agents developed for specific viral protein targets may exhibit broad-spectrum antiviral activity or provide helpful information for broad-spectrum drug development. In this study, we compared the sequence- and structure-based similarity of SARS-CoV-2 3CL^pro with proteases from other viruses and identified 24 proteases with similar active-site structures. Our in-house lead molecules, NIP-22c and CIP-1 were reported as novel peptidomimetic, reversible covalent inhibitors of SARS-CoV-2 3CL^pro with nanomolar potency. Molecular docking of NIP-22c, CIP-1 and nirmatrelvir were performed with structurally similar proteases of different viruses, norovirus, enterovirus and rhinovirus. The predictions were validated with in vitro enzymatic and cell-based assays. As predicted, NIP-22c and CIP-1 showed broad-spectrum antiviral activity with EC₅₀ values in the nanomolar range against SARS-CoV-2, norovirus, enterovirus and rhinovirus by targeting 3CL/3C^pro. In contrast, nirmatrelvir did not show activity up to 10 μM against all three viruses and the mechanism of inactivity of nirmatrelvir was hypothesized through binding pocket analysis using molecular dynamics simulations.

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利用硅结构建模和细胞分析发现针对病毒蛋白酶的广谱抗病毒药物

开发广谱抗病毒药物是预防未来全球疫情的高度优先目标。一些针对特定病毒蛋白靶点开发的抗病毒药物可能表现出广谱抗病毒活性或为广谱药物开发提供有用的信息。在这项研究中，我们比较了SARS-CoV-2 3CLpro与其他病毒蛋白酶的序列和结构相似性，并鉴定出24种具有相似活性位点结构的蛋白酶。据报道，我们的内部铅分子NIP-22c和CIP-1是具有纳米级效力的新型肽类可逆性共价sars - cov - 23clpro抑制剂。将NIP-22c、CIP-1和nirmatrelvir与不同病毒（诺如病毒、肠病毒和鼻病毒）结构相似的蛋白酶进行分子对接。这些预测通过体外酶和细胞实验得到了验证。结果表明，NIP-22c和CIP-1对SARS-CoV-2、诺如病毒、肠道病毒和鼻病毒具有广谱抗病毒活性，EC50值在纳摩尔范围内。相比之下，nirmatrelvir对这三种病毒的活性均不超过10 μM，并通过分子动力学模拟的结合袋分析假设了nirmatrelvir无活性的机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.