Liu Xianglan, Hu Jiaming, Wu Jiarui, Tian Yiru, Wang Jinbo, Wu Chunyan, Chen Qingfeng, Krall Leonard, He Yanping, Lu Qun
Center for Life Sciences, School of Life Sciences, Yunnan Key Laboratory of Cell Metabolism and Diseases, Yunnan University, Kunming, Yunnan, China.
School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong, China.
Virol J. 2025 Apr 4;22(1):93. doi: 10.1186/s12985-025-02687-w.
Human norovirus (HNV) is the predominant pathogen causing outbreaks of acute gastroenteritis globally. Despite significant efforts to combat norovirus infections, there is currently no FDA approved vaccine or antiviral drug available. Consequently, the development of effective antiviral agents is of critical importance.
In this study, a series of 41 5-cyano-2-thiacetyl aromatic pyrimidinone compounds were designed and synthesized. A cell viability-based screening for anti-murine norovirus (MNV) compounds was conducted, revealing that compound 29 (hereafter used as Co-29) exhibited antiviral activity against MNV. Co-29 demonstrated effective inhibition of MNV RNA replication, exhibiting an EC of 58.22 μM. An RdRp enzyme activity assay indicated that Co-29 directly inhibits RdRp activity to both MNV and HNV. Molecular docking studies suggested that Co-29 interacts with the palm region of RdRp via hydrogen bonding with specific residues, which are conserved in RdRps across MNV and HNV norovirus variants.
In conclusion, our study suggests that the newly synthesized Co-29 may serve as a potential antiviral candidate or lead compound for future studies.
人诺如病毒（HNV）是全球范围内引起急性胃肠炎暴发的主要病原体。尽管在对抗诺如病毒感染方面付出了巨大努力，但目前尚无美国食品药品监督管理局（FDA）批准的疫苗或抗病毒药物。因此，开发有效的抗病毒药物至关重要。
在本研究中，设计并合成了一系列41种5-氰基-2-硫代乙酰基芳基嘧啶酮化合物。进行了基于细胞活力的抗小鼠诺如病毒（MNV）化合物筛选，结果显示化合物29（以下简称Co-29）对MNV具有抗病毒活性。Co-29对MNV RNA复制表现出有效抑制作用，其半数有效浓度（EC）为58.22μM。RNA依赖性RNA聚合酶（RdRp）酶活性测定表明，Co-29直接抑制MNV和HNV的RdRp活性。分子对接研究表明，Co-29通过与特定残基形成氢键与RdRp的手掌区域相互作用，这些残基在MNV和HNV诺如病毒变体的RdRp中保守。
总之，我们的研究表明新合成的Co-29可能作为潜在的抗病毒候选物或用于未来研究的先导化合物。
