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Discovery of Small Molecules Against Foot-and-Mouth Disease Virus Replication by Targeting 2C Helicase Activity

文献类型： 外文期刊

作者： Zhou, Saisai 1 ; Mu, Suyu 3 ; Yu, Shuqi 1 ; Tian, Yang 1 ; Lu, Sijia 1 ; Li, Zhen 1 ; Wu, Hao 1 ; Zhao, Jiaying 1 ; Chen, Huanchun 1 ; Sun, Shiqi 3 ; Song, Yunfeng 1 ;

作者机构： 1.Huazhong Agr Univ, State Key Lab Agr Microbiol, Wuhan 430070, Peoples R China

2.Huazhong Agr Univ, Coll Vet Med, Wuhan 430070, Peoples R China

3.Chinese Acad Agr Sci, Lanzhou Vet Res Inst, Lanzhou 730046, Peoples R China

关键词： FMDV; 2C protein; helicase; antiviral inhibitor

期刊名称：VIRUSES-BASEL （ 影响因子：3.5； 五年影响因子：3.7 ）

ISSN：

年卷期： 2025 年 17 卷 6 期

页码：

收录情况： SCI

摘要： Background: The 2C protein of foot-and-mouth disease virus (FMDV), a member of helicase superfamily 3 (SF3), drives viral genome replication and serves as a critical target for antiviral drug development. Methods: A fluorescence resonance energy transfer (FRET)-based high-throughput screening (HTS) platform was developed to identify 2C helicase inhibitors. Primary screening evaluated 4424 compounds for helicase inhibition. Molecular docking analyzed inhibitor interactions with the N207 residue within the catalytic core and helicase inhibition assays classified the inhibitor type (mixed, competitive, noncompetitive). Differential scanning fluorimetry (nanoDSF) quantified 2C thermal destabilization. Antiviral activity was assessed via indirect immunofluorescence, RT-qPCR, and plaque reduction assays. Results: Six compounds inhibited 2C helicase activity at >620 mu M. Molecular docking revealed hydrogen bonding, hydrophobic interactions, and pi-cation stabilization at the catalytic core. 2-MPO and MPPI were classified as mixed-type inhibitors, 5-TzS(-) and 2-PyOH as competitive, and DCMQ/Spiro-BD-CHD-dione as noncompetitive. NanoDSF showed a Delta T-m >= 1.5 degrees C (2.5 mM compounds), with reduced destabilization in N207A mutants. Antiviral assays identified 2-MPO and MPPI as optimal inhibitors. MPPI achieved effective FMDV suppression at 160 mu M, exhibiting two orders of magnitude higher potency than 2-MPO (400 mu M). Conclusions: The established FRET-based HTS platform targeting 2C helicase facilitates anti-FMDV lead discovery, while 2C inhibitors may serve as an effective therapeutic strategy against other picornaviruses.

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