Emerging flaviviruses are causative agents of severe and life-threatening diseases, against which no approved therapies are available. Among the nucleoside analogues, which represent a promising group of potentially therapeutic compounds, fluorine-substituted nucleosides are characterized by unique structural and functional properties. Despite having first been synthesized almost 5 decades ago, they still offer new therapeutic opportunities as inhibitors of essential viral or cellular enzymes active in nucleic acid replication/transcription or nucleoside/nucleotide metabolism. Here, we report evaluation of the antiflaviviral activity of 28 nucleoside analogues, each modified with a fluoro substituent at different positions of the ribose ring and/or heterocyclic nucleobase. Our antiviral screening revealed that 3′-deoxy-3′-fluoroadenosine exerted a low-micromolar antiviral effect against tick-borne encephalitis virus (TBEV), Zika virus, and West Nile virus (WNV) (EC₅₀ values from 1.1 ± 0.1 μM to 4.7 ± 1.5 μM), which was manifested in host cell lines of neural and extraneural origin. The compound did not display any measurable cytotoxicity up to concentrations of 25 μM but had an observable cytostatic effect, resulting in suppression of cell proliferation at concentrations of >12.5 μM. Novel approaches based on quantitative phase imaging using holographic microscopy were developed for advanced characterization of antiviral and cytotoxic profiles of 3′-deoxy-3′-fluoroadenosine in vitro. In addition to its antiviral activity in cell cultures, 3′-deoxy-3′-fluoroadenosine was active in vivo in mouse models of TBEV and WNV infection. Our results demonstrate that fluoro-modified nucleosides represent a group of bioactive molecules with excellent potential to serve as prospective broad-spectrum antivirals in antiviral research and drug development.

中文翻译：

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3'-Deoxy-3'-Fluoroadenosine对新兴黄病毒的广谱抗病毒活性。

新兴的黄病毒是严重且威胁生命的疾病的病原体，目前尚无针对性的批准疗法。在代表有希望的潜在治疗化合物组的核苷类似物中，氟取代的核苷的特征在于独特的结构和功能特性。尽管在将近5年前就已经进行了合成，但它们仍是新的治疗方法，可作为在核酸复制/转录或核苷/核苷酸代谢中具有活性的必需病毒或细胞酶的抑制剂。在这里，我们报告评估的28个核苷类似物的抗黄病毒活性，每个类似物在核糖环和/或杂环核碱基的不同位置上都被氟取代基修饰。从1.1±0.1μM到4.7±1.5μM的_50个值）在神经和神经外来源的宿主细胞系中表现出来。该化合物在浓度达到25μM时未显示任何可测量的细胞毒性，但具有可观察到的细胞抑制作用，从而在浓度> 12.5μM时抑制了细胞增殖。发展了基于全息显微镜定量相成像的新方法，用于体外表征3'-脱氧-3'-氟腺苷的抗病毒和细胞毒性谱。3'-脱氧-3'-氟腺苷除了在细胞培养中具有抗病毒活性外，在体内也具有活性在TBEV和WNV感染的小鼠模型中。我们的结果表明，氟修饰的核苷代表一组具有出色潜力的生物活性分子，可在抗病毒研究和药物开发中用作预期的广谱抗病毒剂。