Antiviral research最新文献_第4页

The natural polyphenol proanthocyanidin A2 prevents the in vitro infection of Ebola virus and rabies virus by interfering with the early phases of the replication cycle 天然多酚原花青素A2通过干扰复制周期的早期阶段阻止埃博拉病毒和狂犬病毒的体外感染

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-11-20 DOI: 10.1016/j.antiviral.2025.106312

Denis Pasqual , Ilaria Artusi , Michele Paccagnella , Giulia Sibille , Mattia Mirandola , Sofia Appelberg , Maria Francesca Priore , Maira Zorzan , Massimo E. Maffei , Paola De Benedictis , Claudia Del Vecchio , Alì Mirazimi , Giorgio Cozza , Giorgio Gribaudo , Cristiano Salata

The Ebola virus (EBOV) and the Rabies virus (RABV) are deadly infectious agents impacting human and animal health. Current prevention and control strategies mainly rely on vaccines and antibodies, highlighting the urgent need for effective, low-cost antivirals suitable for therapeutic options. Plant-derived bioactive compounds offer a promising natural source for such candidate antivirals. As a contribution to this antiviral approach, we have characterized the anti-EBOV and anti-RABV activity of a Cranberry extract (CE) endowed with a very high content of bioactive A2-type proanthocyanidin (PAC-A2). The CE inhibited the in vitro infection of both pseudoviruses expressing EBOV-GP or RABV-G glycoproteins and authentic EBOV and RABV. Attachment and entry assays revealed that the extract targets early phases of infection preventing attachment and entry. Noteworthy, synthetic PAC-A2 reproduced the antiviral activity observed with the whole CE. Mechanistic studies then revealed that the CE interacted directly with the ectodomain of EBOV-GP or the RABV-G, suggesting interference with their functions. In support to this hypothesis, fluorescence spectroscopy analysis showed a reduction in intrinsic fluorescence of both EBOV-GP and RABV-G after incubation with synthetic PAC-A2, thus confirming a direct interaction of the viral glycoproteins with PAC-A2. In silico docking simulations further sustained in vitro results by predicting the binding of PAC-A2 into the binding pocket of EBOV-GP and to the trimeric architecture of RABV-G.

Together, these results suggest this cranberry extract and bioactive PAC-A2 as potential candidates to be further develop as novel antiviral agents for the prevention of EBOV and RABV infections.

埃博拉病毒（EBOV）和狂犬病毒（RABV）是影响人类和动物健康的致命传染病。目前的预防和控制战略主要依靠疫苗和抗体，这突出表明迫切需要适用于治疗方案的有效、低成本抗病毒药物。植物源性生物活性化合物为这类候选抗病毒药物提供了一个很有前途的天然来源。作为对这种抗病毒方法的贡献，我们已经鉴定了具有非常高含量的生物活性a2型原花青素（PAC-A2）的蔓越莓提取物（CE）的抗ebov和抗rabv活性。CE对表达EBOV- gp或RABV- g糖蛋白的假病毒和真EBOV和RABV的体外感染均有抑制作用。附着和进入试验表明，提取物针对感染的早期阶段，防止附着和进入。值得注意的是，合成PAC-A2复制了整个CE所观察到的抗病毒活性。机制研究表明，CE直接与EBOV-GP或RABV-G的外畴相互作用，表明其功能受到干扰。为了支持这一假设，荧光光谱分析显示，EBOV-GP和RABV-G与合成的PAC-A2一起培养后，其固有荧光减少，从而证实了病毒糖蛋白与PAC-A2的直接相互作用。通过预测PAC-A2与EBOV-GP结合口袋和RABV-G三聚体结构的结合，硅对接模拟进一步支持了体外结果。综上所述，这些结果表明蔓越莓提取物和具有生物活性的PAC-A2具有进一步开发的潜力，可作为预防EBOV和RABV感染的新型抗病毒药物。

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引用次数: 0

Targeted inhibition of IGF2BP1 effectively suppresses HBV replication via an m6A-dependent manner 靶向抑制IGF2BP1通过m6a依赖的方式有效抑制HBV复制。

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-11-20 DOI: 10.1016/j.antiviral.2025.106310

Deyao Li , Yuxin Song , Danjuan Lu , Yanhua Zhang , Chenxiao Qu , Guiwen Guan , Yuexi Ma , Tianhao Mao , Liwei Zheng , Yi Wang , Wenhui Song , Ting Zhang , Fengmin Lu , Jing Ning , Xiangmei Chen

Elucidation of the regulation mechanism of hepatitis B virus (HBV) replication will provide potential targets for the development of novel anti-HBV therapeutics. It has been reported that the N6-methyladenosine (m6A) modification of HBV RNA plays a crucial role in the HBV life cycle. However, the mechanisms underlying the regulation of this modification remain incompletely understood. In this study, combining loss- and gain-of-function genetic analyses, we defined the role of IGF2BP1, an m6A reader, in facilitating HBV replication. Mechanistic studies revealed that IGF2BP1 stabilizes HBV RNAs primarily by binding to m6A-modified A1907 sites through its KH3-4 domain, thereby enhancing viral replication. Furthermore, targeted inhibition of IGF2BP1 by Cucurbitacin B, a small molecule inhibitor of IGF2BP1, was shown to inhibit HBV replication in vitro and in vivo. Taken together, these findings identify IGF2BP1 as a critical host regulator of HBV RNA stability through an m6A-dependent manner and targeted inhibition of IGF2BP1 effectively attenuates viral replication, providing a promising strategy for anti-HBV drug development.

阐明乙型肝炎病毒（HBV）复制的调控机制将为开发新型抗HBV治疗药物提供潜在靶点。据报道，HBV RNA的n6 -甲基腺苷（m6A）修饰在HBV生命周期中起着至关重要的作用。然而，这种修饰的调控机制仍然不完全清楚。在这项研究中，结合功能丧失和功能获得的遗传分析，我们确定了IGF2BP1（一种m6A读取器）在促进HBV复制中的作用。机制研究表明，IGF2BP1主要通过其KH3-4结构域结合m6a修饰的A1907位点来稳定HBV rna，从而增强病毒复制。此外，IGF2BP1的小分子抑制剂葫芦素B靶向抑制IGF2BP1，在体外和体内均可抑制HBV复制。综上所述，这些发现确定了IGF2BP1是HBV RNA稳定性的关键宿主调节剂，通过m6a依赖的方式和靶向抑制IGF2BP1有效地减弱病毒复制，为抗HBV药物开发提供了一个有希望的策略。在本研究中，我们发现宿主因子IGF2BP1通过其KH结构域，主要通过识别和结合HBV RNA上的m6A修饰位点来增强所有五种HBV RNA的稳定性，从而促进HBV RNA的表达和HBV复制。葫芦素B是IGF2BP1的小分子抑制剂，可通过降低HBV RNA表达有效抑制HBV复制，为抗HBV药物的开发提供了新的途径。

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引用次数: 0

Bulevirtide for chronic hepatitis delta: from clinical trials to real life data: an expert opinion report 布来韦肽治疗慢性丁型肝炎：从临床试验到现实生活数据：专家意见报告。

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-11-19 DOI: 10.1016/j.antiviral.2025.106311

Tarik Asselah , Homie Razavi , Hélène Fontaine , Kosh Agarwal

Hepatitis D virus (HDV) is a small RNA virus that requires Hepatitis B Surface Antigen (HBsAg) for its envelope. Eight genotypes with more than 80 % sequence homology and many subgenotypes have been described. Worldwide prevalence of chronic hepatitis delta (CHD) is estimated at about 5 % of chronic hepatitis B cases, translating to 15–20 million individuals. The diagnosis of HDV infection involves presence of antibodies to hepatitis D antigen (anti-HDV antibodies). Anti-HDV total antibody indicates HDV exposure (not infection). To document infection; the patient needs to undergo PCR testing and only if PCR is positive should the diagnosis of HDV ongoing infection done. Testing for the antibodies should be performed in all HBsAg-positive persons. CHD is more severe and progressive than HBV mono-infection, with a higher risk of cirrhosis and hepatocellular carcinoma (HCC), transplantation and death. Pegylated interferon-alpha (pegIFN-a) has been used for treating CHD with only limited durable responses. A 48-week course of weekly subcutaneous injections of pegIFN-a suppresses HDV replication in approximately 20–30 % of patients 24 weeks off therapy, with significant side effects. Bulevirtide (BLV) was approved by the European Medicines Agency (EMA) in 2020 for CHD and compensated liver disease. Since its approval, real-life data on the use of BLV have been accumulating, with most treated patients in Europe having advanced fibrosis or cirrhosis. Real life data efficacy is concordant to that seen in clinical trials, with many patients achieving significant reductions in HDV RNA levels and ALT normalization after several months of treatment, and favorable safety. However, HBsAg loss is relatively rare. Finite therapy of BLV, in combination with pegIFN-a, leads to significant durable response, with more than 30 % of patients achieving HDV RNA undetectability off therapy. We need new finite therapies. Further real-world data and newer therapies are required for this severe disease.

丁型肝炎病毒（HDV）是一种小RNA病毒，其包膜需要乙型肝炎表面抗原（HBsAg）。目前已发现8种序列同源性超过80%的基因型和许多亚基因型。据估计，全球慢性丁型肝炎（CHD）患病率约占慢性乙型肝炎病例的5%，相当于1500万至2000万人。丁型肝炎病毒感染的诊断包括存在丁型肝炎抗原抗体（抗丁型肝炎病毒抗体）。抗HDV总抗体表明HDV暴露（不是感染）。记录感染；患者需要进行聚合酶链反应检测，只有当聚合酶链反应呈阳性时，才应诊断为HDV持续感染。应对所有hbsag阳性的人进行抗体检测。冠心病比单HBV感染更严重和进展，肝硬化和肝细胞癌（HCC）、移植和死亡的风险更高。聚乙二醇化干扰素- α (pegIFN-a)已被用于治疗冠心病，但只有有限的持久反应。每周一次皮下注射pegIFN-a的48周疗程可以抑制约20-30%的患者在治疗24周后的HDV复制，但有明显的副作用。Bulevirtide （BLV）于2020年获得欧洲药品管理局（EMA）批准，用于治疗冠心病和代偿性肝病。自批准以来，BLV的实际使用数据一直在积累，欧洲大多数接受治疗的患者患有晚期纤维化或肝硬化。现实生活数据疗效与临床试验一致，许多患者在治疗几个月后HDV RNA水平和ALT正常化显著降低，安全性良好。然而，HBsAg损失相对罕见。有限的BLV治疗，结合pegIFN-a，导致显著的持久反应，超过30%的患者在治疗后达到HDV RNA不可检测。我们需要新的有限疗法。这种严重疾病需要进一步的真实世界数据和更新的治疗方法。

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引用次数: 0

Genetic determinants of efficacy of antiviral drugs revealed by genome-wide CRISPR screens 全基因组CRISPR筛选揭示抗病毒药物疗效的遗传决定因素。

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-11-17 DOI: 10.1016/j.antiviral.2025.106309

Wei Jiang , Ailing Yang , Jingchuan Ma , Dawei Lv , Mingxian Liu , Chao Wang , Shuo Chen , Huiling Fang , Yankai Chu , Zhengjin He , Wenrui Li , Yucheng Liu , Yun Zhao , Zhaocai Zhou , Gang Long , Hai Jiang

Nucleoside and nucleobase analog antiviral drugs are pivotal in antiviral therapy, but comprehensive methods to understand their cellular response mechanisms and genetic regulators are still lacking. Here, we show that Eμ-Myc; Arf^−/− mouse lymphoma cells, which are highly apoptosis-prone, enabled genome-wide CRISPR-Cas9 screening on such drugs to identify genes that modulate their efficacy. Using retroviral sgRNA libraries and MAGeCK analysis, we uncovered key regulators of drug transport, activation, and inactivation for these drugs. For ribavirin, adenosine kinase (ADK) and adenylsuccinate synthase (ADSS) were critical for nucleotide metabolism and bioactivation. Remdesivir uptake and activation depended on the transporter SLC29A3 and phosphoamidase HINT1, whereas favipiravir resistance was linked to NT5C2-mediated dephosphorylation. Viral replication assays in Huh7 cells validated that knockout of SLC29A3, HINT1, or NT5C2 significantly altered antiviral efficacy. This study delineates the genetic network governing nucleotide analog response, providing mechanistic insights and potential biomarkers for personalized antiviral therapy.

核苷和核碱基类似物抗病毒药物是抗病毒治疗的关键，但了解其细胞反应机制和遗传调控因子的综合方法仍然缺乏。这里，我们证明了Eμ-Myc；Arf-/-小鼠淋巴瘤细胞是高度凋亡易感性的细胞，因此可以对这些药物进行全基因组CRISPR-Cas9筛选，以确定调节其疗效的基因。利用逆转录病毒sgRNA文库和MAGeCK分析，我们发现了这些药物转运、激活和失活的关键调控因子。对于利巴韦林，腺苷激酶（ADK）和腺苷琥珀酸合成酶（ADSS）是核苷酸代谢和生物活化的关键。瑞德西韦的摄取和激活依赖于转运体SLC29A3和磷酸化酶HINT1，而法匹拉韦耐药与nt5c2介导的去磷酸化有关。Huh7细胞中的病毒复制实验证实，敲除SLC29A3、HINT1或NT5C2显著改变了抗病毒效果。这项研究描述了控制核苷酸类似物反应的遗传网络，为个性化抗病毒治疗提供了机制见解和潜在的生物标志物。

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引用次数: 0

Lyophilization enables thermostable formulation of dengue virus-derived defective interfering particles 冻干使登革病毒衍生的缺陷干扰颗粒的热稳定性配方成为可能。

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-11-08 DOI: 10.1016/j.antiviral.2025.106308

Min-Hsuan Lin , Pramila Maniam , Bing Tang , David Harrich

Defective interfering particles (DIPs), containing truncated defective viral genomes (DVGs), are natural byproducts of RNA virus replication with potent antiviral activity. We recently developed a virus-free, dengue virus (DENV)-based platform producing antiviral DIPs with DI290 DVG, termed DIP-DI290. In this study, we established a scalable purification and lyophilization workflow for creating thermostable DIP-DI290 formulations for long-term storage. DIP-DI290 particles were purified via tangential flow filtration and ceramic hydroxyapatite chromatography, then lyophilized and reconstituted for biological assessment. After three months of storage at −80 °C, 4 °C, or room temperature, reconstituted DIP-DI290 retained biological activity, significantly upregulating interferon-stimulated genes (ISGs) and suppressing DENV-2 replication. These findings demonstrate that lyophilization preserves DIP-DI290's antiviral efficacy across diverse storage conditions, supporting its development as a thermostable, field-deployable therapeutic platform for virus infections.

含有截断缺陷病毒基因组（dvg）的缺陷干扰颗粒（dip）是RNA病毒复制的天然副产物，具有强大的抗病毒活性。我们最近开发了一种无病毒、基于登革热病毒（DENV）的平台，生产含有DI290 DVG的抗病毒dip，称为DIP-DI290。在这项研究中，我们建立了一个可扩展的纯化和冻干工作流程，用于创建长期储存的耐热DIP-DI290配方。DIP-DI290颗粒经切向流过滤和陶瓷羟基磷灰石层析纯化，然后冻干重组用于生物学评价。在-80°C、4°C或室温下保存三个月后，重组DIP-DI290保留了生物活性，显著上调干扰素刺激基因（ISGs）并抑制DENV-2复制。这些研究结果表明，冻干保存DIP-DI290在不同储存条件下的抗病毒功效，支持其作为耐热、可现场部署的病毒感染治疗平台的发展。

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引用次数: 0

Biology of hepatitis B virus DNA integration and its impact on antiviral R&D 乙型肝炎病毒DNA整合生物学及其对抗病毒药物研发的影响

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-11-04 DOI: 10.1016/j.antiviral.2025.106305

Lottida Phondeth , Thomas Tu

Hepatitis B virus (HBV) drastically increases the risk of developing liver cirrhosis and hepatocellular carcinoma (HCC) in the ∼300 million people with chronic hepatitis B infections. HBV reproduces through an epigenetic circular genome, but can occasionally integrate into the host genome as a replication-defective form. These integrated forms have been reported to contribute to virus persistence and hepatocarcinogenesis. In this review, we highlight the effects of current and novel treatment under development on HBV DNA integrations and provide areas of potential research to develop more effective therapies that target the underlying drivers of persistence and pathogenesis.

乙型肝炎病毒（HBV）大大增加了约3亿慢性乙型肝炎感染者发生肝硬化和肝细胞癌（HCC）的风险。HBV通过表观遗传环状基因组繁殖，但偶尔也会以复制缺陷形式整合到宿主基因组中。据报道，这些整合形式有助于病毒的持久性和肝癌的发生。在这篇综述中，我们强调了当前和正在开发的新型治疗方法对HBV DNA整合的影响，并提供了潜在的研究领域，以开发针对持久性和发病机制的潜在驱动因素的更有效的治疗方法。

引用次数: 0

A dual-reporter HCoV-OC43 for coronavirus biology and countermeasure development 新型冠状病毒生物学双报告型HCoV-OC43及其对策研究

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-11-04 DOI: 10.1016/j.antiviral.2025.106306

Xiangxue Deng , Jing Zou , Zhenjie Liang , Ping Ren , Pei-Yong Shi , Vineet D. Menachery , Xuping Xie

A reliable experimental system is essential for advancing coronavirus biology and expediting countermeasure development. In this study, we report the construction of an infectious clone of human coronavirus OC43 (HCoV-OC43) using an in vitro ligation strategy. The clone-derived virus faithfully recapitulates the replication characteristics of the parental isolate in vitro. Leveraging this platform, we have developed a dual-reporter virus, OC43-mNG-Nluc, by replacing the viral accessory gene ns2 with a gene cassette encoding both nanoluciferase and fluorescent protein mNeonGreen. This construct enables dual-mode detection via chemiluminescence and fluorescence within a single assay. OC43-mNG-Nluc maintains replication kinetics identical to wild-type HCoV-OC43 in standard immortalized cell lines but exhibits marked attenuation in primary human airway epithelial cultures, underscoring the critical role of ns2 in viral replication within physiologically relevant systems. The dual-reporter virus also demonstrates excellent genetic and phenotypic stability following fifteen passages in vitro. Furthermore, we validate the proof-of-concept utility of OC43-mNG-Nluc in high-throughput antiviral screening, showcasing its advantages in streamlining and facilitating hit identification, triaging, and prioritization. Collectively, this study provides valuable insights into HCoV-OC43 biology and introduces a versatile and robust tool for coronavirus research and therapeutic development.

可靠的实验系统是推进冠状病毒生物学和加快对策制定的必要条件。在这项研究中，我们报告了使用体外结扎策略构建人类冠状病毒OC43的感染性克隆。克隆衍生病毒在体外忠实地再现了亲本分离物的复制特性。利用这一平台，我们开发了一种双报告病毒，oc43 - mg - nluc，通过用编码纳米荧光素酶和荧光蛋白mNeonGreen的基因盒取代病毒的辅助基因ns2。这种结构使双模式检测通过化学发光和荧光在一个单一的分析。在标准永生化细胞系中，OC43- mg - nluc保持与野生型OC43相同的复制动力学，但在原代人气道上皮培养物中表现出明显的衰减，强调了ns2在生理相关系统中病毒复制中的关键作用。在体外15次传代后，双报告病毒也表现出良好的遗传和表型稳定性。此外，我们验证了OC43-mNG-Nluc在高通量抗病毒筛选中的概念验证效用，展示了其在简化和促进命中识别、分诊和优先排序方面的优势。总的来说，这项研究为HCoV-OC43生物学提供了有价值的见解，并为冠状病毒的研究和治疗开发引入了一个多功能和强大的工具。

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引用次数: 0

Repurposed doxepin targeting host AXL kinase to disrupt viral 2C-mediated immune evasion in Coxsackievirus B infection 重用途多虑平靶向宿主AXL激酶破坏柯萨奇病毒B感染中病毒2c介导的免疫逃避

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-11-04 DOI: 10.1016/j.antiviral.2025.106307

Ran Yan , Qiting Luo , Xinyi Luo , Xinrui Zhou , Jiayi Diao , Jiapeng Xu , Wei Ye , Kai Zheng , Ge Liu , Qinchang Zhu

Coxsackievirus B (CVB) infections pose a significant clinical burden due to their association with severe diseases such as myocarditis and aseptic meningitis, and effective antiviral therapies remain an unmet medical need. Here, we investigated the potential of repurposing doxepin hydrochloride (DH), a tricyclic antidepressant, as an antiviral agent against CVB. Our in vitro and in vivo experiments demonstrated that DH significantly inhibits CVB replication. Mechanistically, we elucidated that DH targets the host AXL kinase, thereby inhibiting its phosphorylation of the viral 2C protein at tyrosine 162. This disruption of 2C phosphorylation abrogates CVB-induced suppression of the host IKKβ/NF-κB signaling pathway, leading to the restoration of innate immune responses and enhanced production of pro-inflammatory cytokines IL-1β and IL-6. Furthermore, our findings unveiled a novel immune evasion mechanism employed by CVB, wherein AXL kinase modulates viral replication by regulating host immune signaling. These results highlight AXL as a critical host factor in CVB infection and provide a strong rationale for considering DH as a potential host-targeted therapeutic strategy for CVB-associated diseases, particularly in the absence of specific antiviral agents.

柯萨奇病毒B （CVB）感染由于与心肌炎和无菌性脑膜炎等严重疾病相关而造成重大的临床负担，有效的抗病毒治疗仍然是未满足的医疗需求。在这里，我们研究了三环抗抑郁药盐酸多虑平（DH）作为CVB抗病毒药物的潜力。我们的体外和体内实验表明，DH显著抑制CVB复制。在机制上，我们阐明了DH靶向宿主AXL激酶，从而抑制其对病毒2C蛋白酪氨酸162的磷酸化。这种2C磷酸化的破坏消除了cvb诱导的宿主IKKβ/NF-κB信号通路的抑制，导致先天免疫应答的恢复和促炎细胞因子IL-1β和IL-6的产生增强。此外，我们的发现揭示了CVB采用的一种新的免疫逃避机制，其中AXL激酶通过调节宿主免疫信号来调节病毒复制。这些结果强调了AXL是CVB感染的关键宿主因子，并为考虑DH作为CVB相关疾病的潜在宿主靶向治疗策略提供了强有力的理由，特别是在缺乏特异性抗病毒药物的情况下。

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引用次数: 0

Design, synthesis and biological evaluation of a novel series of conjugates of N1-(phosphonoalkyl)-1,2,3-triazoles and N3-benzyl-6-bromoquinazoline-2,4-diones with anti-RSV activity 具有抗rsv活性的新型N1-（膦烷基）-1,2,3-三唑和n3 -苄基-6-溴喹唑-2,4-二酮缀合物的设计、合成和生物学评价

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-10-30 DOI: 10.1016/j.antiviral.2025.106303

Iwona E. Głowacka , Mirthe Graus , Dorota G. Piotrowska , Kurt Vermeire

Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory infections and hospitalization in young children, but also poses a significant threat to elderly, high-risk adults, and immuno-compromised patients. Despite major progress regarding vaccines and RSV prophylaxis, the current arsenal of RSV antivirals is very limited. A new series of conjugates of N1-(phosphonoalkyl)-1,2,3-triazoles and 6-bromoquinazoline-2,4-diones functionalized with the 2-, 3- and 4-nitrobenzyl, 3-fluorobenzyl or 3-chlorobenzyl at N3 position of quinazoline-2,4-dione moiety were synthesized and evaluated for their potential antiviral activity. Among all tested compounds, conjugates 1 cb and 1 fb showed the strongest anti-RSV activity (high nanomolar to low micromolar range), both in U87MG and HEp-2 cells and proved to be non-toxic toward the tested cell lines. In addition, compounds (1R,2S)-1ha and (1R,2S)-1hd exhibited moderate activity (high micromolar range) against zika virus in Huh7 cell cultures. The C1-epimeric phosphonates (1S,2S)-1ha and (1S,2S)-1 hb proved to be inactive against the tested viruses, while being highly cytotoxic toward uninfected HEL, Huh-7 and MDCK cell lines. Phosphonic acids derived from the respective diethoxyphosphonyl conjugates showed no activity against the viruses tested, probably due to their poor permeability through cell membranes. In conclusion, our study demonstrates the great potency of the design of conjugates of N1-(phosphonoalkyl)-1,2,3-triazoles and 6-bromoquinazoline-2,4-diones as effective anti-RSV agents and highlights the potential of this compound class as antiviral therapeutics, warranting further structural optimization and in vivo evaluation to develop more potent and selective anti-RSV agents.

呼吸道合胞病毒（RSV）是幼儿急性下呼吸道感染和住院的主要原因，但也对老年人、高危成人和免疫功能低下患者构成重大威胁。尽管在疫苗和RSV预防方面取得了重大进展，但目前的RSV抗病毒药物非常有限。合成了一系列新的N1-（膦烷基）-1,2,3-三唑和6-溴喹唑啉-2,4-二酮缀合物，并在喹唑啉-2,4-二酮的N3位上与2-、3-和4-硝基苯、3-氟苯或3-氯苯官能化，并评价了它们的潜在抗病毒活性。在所测试的化合物中，结合物1cb和1fb在U87MG和HEp-2细胞中均表现出最强的抗rsv活性（高纳摩尔到低微摩尔范围），并且对所测试的细胞系无毒。此外，化合物(1R,2S)-1ha和(1R,2S)-1hd在Huh7细胞培养中对寨卡病毒表现出中等活性（高微摩尔范围）。c1 -外周膦酸盐(1S,2S)-1ha和(1S,2S)-1hb对试验病毒无活性，而对未感染的HEL， Huh-7和MDCK细胞系具有高度的细胞毒性。从二氧膦基偶联物中提取的磷酸对所测试的病毒没有活性，可能是由于它们对细胞膜的渗透性差。总之，我们的研究证明了N1-（膦烷基）-1,2,3-三唑和6-溴喹唑啉-2,4-二酮的偶联物设计作为有效的抗rsv药物的巨大潜力，并强调了这类化合物作为抗病毒治疗药物的潜力，需要进一步的结构优化和体内评估，以开发更有效和选择性的抗rsv药物。

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引用次数: 0

Rapid generation of a murine RSV infectious model by transducing a conditional knock-in mouse harboring human IGF1 receptor with adenoviral vector 用腺病毒载体转导含人IGF1受体的条件敲入小鼠，快速生成小鼠RSV感染模型。

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-10-29 DOI: 10.1016/j.antiviral.2025.106304

Rui Xiong , Yong Wu , Yuya Wang , Zhe Qu , Yanwei Yang , Susu Liu , Chen Ling , Lu Ke , Nan Xu , Changgui Li , Changfa Fan , Yihong Peng

Human respiratory syncytial virus (RSV) remains the leading viral cause of severe lower respiratory tract disease in infants and young children worldwide. Despite decades of research, RSV vaccine development remains hindered by the lack of animal models that accurately recapitulate pediatric susceptibility and allow rigorous assessment of protective efficacy and safety. Recent studies have identified the human insulin-like growth factor 1 receptor (hIGF1R) as a critical host receptor that facilitates RSV fusion and entry. Using a novel conditional knock-in mouse model, lung-specific hIGF1R expression achieved through Ad5 vector transduction enables rapid generation of a pediatric-relevant mouse model, offering a promising route to close this gap. Following intranasal challenge with RSV A2 (1.62 × 10⁵ TCID₅₀), four-week-old Ad5-hIGF1R mice exhibited higher pulmonary viral loads, marked peribronchiolar and perivascular inflammation, interstitial thickening and a tendency toward alveolar wall coalescence compared with wild-type controls, thereby recapitulating severe pediatric RSV disease. Transcriptomic analysis revealed 12 chemokine genes, upregulated in RSV-infected lungs of Ad5-hIGF1R mice relative to mock controls, that are involved in immune-inflammatory pathways and may serve as practical biomarkers for detecting dysregulated host responses during vaccine or antiviral-drug assessment. Furthermore, A mid-dose prefusion F (pre-F) vaccination regimen significantly reduced viral loads and moderately attenuated neutrophil infiltration in the lungs of Ad5-hIGF1R mice. In summary, the young Ad5-hIGF1R mice demonstrate that hIGF1R expression enhances RSV replication and immunopathology in vivo. This model not only overcomes the limited RSV susceptibility of conventional young mice but also provides a platform for evaluating RSV vaccines.

人呼吸道合胞病毒（RSV）仍然是全世界婴幼儿严重下呼吸道疾病的主要病毒病因。尽管进行了数十年的研究，但由于缺乏准确概括儿童易感性并允许严格评估保护效力和安全性的动物模型，RSV疫苗的开发仍然受到阻碍。最近的研究发现，人胰岛素样生长因子1受体（hIGF1R）是促进RSV融合和进入的关键宿主受体。利用一种新的条件敲入小鼠模型，通过Ad5载体转导实现肺特异性hIGF1R表达，能够快速生成儿科相关小鼠模型，为缩小这一差距提供了一条有希望的途径。在RSV A2 （1.62 × 105 TCID50）鼻内攻击后，与野生型对照相比，4周龄Ad5-hIGF1R小鼠表现出更高的肺部病毒载量、明显的细支气管周围和血管周围炎症、间质增厚和肺泡壁合并的倾向，从而再现了严重的儿科RSV疾病。转录组学分析揭示了12种趋化因子基因，它们在rsv感染的Ad5-hIGF1R小鼠的肺部中相对于模拟对照组上调，这些趋化因子基因参与免疫炎症途径，可能作为在疫苗或抗病毒药物评估期间检测失调宿主反应的实用生物标志物。此外，中剂量预融合F （pre-F）疫苗接种方案显著降低了Ad5-hIGF1R小鼠肺部的病毒载量和中度减弱的中性粒细胞浸润。总之，年轻Ad5-hIGF1R小鼠表明，在体内，hIGF1R的表达增强了RSV的复制和免疫病理。该模型不仅克服了传统幼鼠RSV易感性的局限性，而且为RSV疫苗的评价提供了平台。

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