一种 RNA 聚合酶 PA-PB1 相互作用抑制剂与奥司他韦在细胞培养和卵中对人流感病毒和禽流感病毒的协同活性。

IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Antiviral research Pub Date : 2024-08-06 DOI:10.1016/j.antiviral.2024.105980
Anna Bonomini , Jiwei Zhang , Han Ju , Alessia Zago , Martina Pacetti , Oriana Tabarrini , Serena Massari , Xinyong Liu , Beatrice Mercorelli , Peng Zhan , Arianna Loregian
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引用次数: 0

摘要

为了寻找治疗流感病毒(IV)感染的新疗法,我们之前发现了一系列抑制剂,它们通过破坏病毒 RNA 聚合酶 PA 和 PB1 亚基之间的相互作用发挥作用。这些化合物对人类甲型和乙型流感病毒具有广谱抗病毒活性,而且在体外诱导耐药性方面具有很高的屏障作用。在这篇短讯中,我们研究了 PA-PB1 相互作用抑制剂 54 与羧酸奥司他韦 (OSC)、扎那米韦 (ZA)、法非拉韦 (FPV) 和巴洛沙韦 marboxil (BXM) 的组合对体外甲型和乙型流感病毒复制的抑制作用。我们观察到 54/OSC 和 54/ZA 组合具有协同作用,而 54 与 FPV 或 BXM 组合则具有拮抗作用。此外,我们还在细胞培养和胚胎鸡卵模型中证实了 54 对禽流感 IV 株的疗效。最后,我们还观察到,在鸡胚蛋模型中,54 能增强 OSC 对禽 IV 型病毒复制的保护作用。我们的研究结果标志着在开发针对人类和禽类 IV 型病毒感染的替代治疗策略方面取得了进展。
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Synergistic activity of an RNA polymerase PA-PB1 interaction inhibitor with oseltamivir against human and avian influenza viruses in cell culture and in ovo

In search of novel therapeutic options to treat influenza virus (IV) infections, we previously identified a series of inhibitors that act by disrupting the interactions between the PA and PB1 subunits of the viral RNA polymerase. These compounds showed broad-spectrum antiviral activity against human influenza A and B viruses and a high barrier to the induction of drug resistance in vitro. In this short communication, we investigated the effects of combinations of the PA-PB1 interaction inhibitor 54 with oseltamivir carboxylate (OSC), zanamivir (ZA), favipiravir (FPV), and baloxavir marboxil (BXM) on the inhibition of influenza A and B virus replication in vitro. We observed a synergistic effect of the 54/OSC and 54/ZA combinations and an antagonistic effect when 54 was combined with either FPV or BXM. Moreover, we demonstrated the efficacy of 54 against highly pathogenic avian influenza viruses (HPAIVs) both in cell culture and in the embryonated chicken eggs model. Finally, we observed that 54 enhances OSC protective effect against HPAIV replication in the embryonated eggs model. Our findings represent an advance in the development of alternative therapeutic strategies against both human and avian IV infections.

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来源期刊
Antiviral research
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.
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