A study of flavonoid inhibitors against Monkeypox H1 phosphatase.

IF 5.4 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Hwa Young Kim, Mi-Sun Kim, Dong Hae Shin
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引用次数: 0

Abstract

Poxviruses regulate their replication cycle through host phosphorylation pathways, with dual-specific phosphatase H1(DUSP-H1) playing a key role in immune evasion by dephosphorylating STAT1 and inhibiting interferon(IFN) responses. Given its high conservation across orthopoxviruses, it represents a promising antiviral target. This study screened a flavonoid library against DUSP-H1 from monkeypox virus (mDUSP-H1) using a malachite green-based phosphatase assay, identifying Myricetin, (-)-Gallocatechin, Cupressuflavone, (-)-Epigallocatechin gallate, Baicalein, and Herbacetin as potent mDUSP-H1 inhibitors (IC50: 7.07-14.05 μM). Docking analysis revealed key hydrogen bonding interactions between 5,7-hydroxyl groups of the hydroxyflavone backbone and Asp79 and Arg116 of mDUSP-H1, respectively. Additional interactions with Ser23 via the 3'-hydroxyl group seems to enhance binding and effectively blocking the enzyme's active site. These findings align with previous studies on tyrosine phosphatase inhibitors, supporting flavonoids as broad-spectrum viral phosphatase inhibitors. Further structural and pharmacokinetic studies will aid in developing optimised antiviral therapies against monkeypox, variola, and cowpox viruses.

猴痘H1磷酸酶类黄酮抑制剂的研究。
痘病毒通过宿主磷酸化途径调节其复制周期,双特异性磷酸酶H1(DUSP-H1)通过去磷酸化STAT1和抑制干扰素(IFN)应答在免疫逃避中发挥关键作用。鉴于其在正痘病毒中的高度保守性,它代表了一个有希望的抗病毒靶点。本研究利用孔雀石绿为基础的磷酸酶试验,筛选了抗猴痘病毒DUSP-H1 (mDUSP-H1)的类黄酮文库,鉴定出杨梅素、(-)-没食子儿茶素、苏木黄酮、(-)-表没食子儿茶素没食子酸酯、黄芩素和Herbacetin是有效的mDUSP-H1抑制剂(IC50: 7.07-14.05 μM)。对接分析揭示了羟黄酮骨架的5,7-羟基分别与mDUSP-H1的Asp79和Arg116之间的关键氢键相互作用。通过3'-羟基与Ser23的其他相互作用似乎增强了结合并有效地阻断了酶的活性位点。这些发现与之前对酪氨酸磷酸酶抑制剂的研究一致,支持黄酮类化合物作为广谱病毒磷酸酶抑制剂。进一步的结构和药代动力学研究将有助于开发针对猴痘、天花和牛痘病毒的最佳抗病毒疗法。
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
CiteScore
10.30
自引率
10.70%
发文量
195
审稿时长
4-8 weeks
期刊介绍: Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.
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