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Anti-SARS-CoV-2 gapmer antisense oligonucleotides targeting the main protease region of viral RNA 针对病毒 RNA 主要蛋白酶区的抗 SARS-CoV-2 gapmer 反义寡核苷酸。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-23 DOI: 10.1016/j.antiviral.2024.105992
Masako Yamasaki , Wakana Saso , Takuya Yamamoto , Masayoshi Sato , Hiroko Takagi , Tetsuya Hasegawa , Yuji Kozakura , Hiroyuki Yokoi , Hirofumi Ohashi , Kana Tsuchimoto , Rina Hashimoto , Shuetsu Fukushi , Akihiko Uda , Masamichi Muramatsu , Kazuo Takayama , Ken Maeda , Yoshimasa Takahashi , Tsuyoshi Nagase , Koichi Watashi

Given the worldwide risk for the outbreak of emerging/re-emerging respiratory viruses, establishment of new antiviral strategies is greatly demanded. In this study, we present a scheme to identify gapmer antisense oligonucleotides (ASOs) targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA that efficiently inhibit viral replication. We synthesized approximately 300 gapmer ASOs designed to target various SARS-CoV-2 RNA regions and evaluated their activity in cell-based assays. Through a multistep screening in cell culture systems, we identified that ASO#41, targeting the coding region for viral main protease, reduced SARS-CoV-2 RNA levels in infected cells and inhibited virus-induced cytopathic effects. Antiviral effect of ASO#41 was also observed in iPS cell-derived human lung organoids. ASO#41 depleted intracellular viral RNAs during genome replication in an endogenous RNaseH-dependent manner. ASO#41 showed a wide range of antiviral activity against SARS-CoV-2 variants of concern including Alpha, Delta, and Omicron. Intranasal administration to mice exhibited intracellular accumulation of ASO#41 in the lung and significantly reduced the viral infectious titer, with milder body weight loss due to SARS-CoV-2 infection. Further chemical modification with phosphoryl guanidine-containing backbone linkages provided an elevation of anti-SARS-CoV-2 activity, with 23.4 nM of 50% antiviral inhibitory concentration, one of the strongest anti-SARS-CoV-2 ASOs reported so far. Our study presents an approach to identify active ASOs against SARS-CoV-2, which is potentially useful for establishing an antiviral strategy by targeting genome RNA of respiratory viruses.

鉴于新发/再发呼吸道病毒在全球范围内爆发的风险,建立新的抗病毒策略是非常必要的。在本研究中,我们提出了一种方案,以识别能有效抑制病毒复制的、靶向严重急性呼吸系统综合征冠状病毒 2(SARS-CoV-2)RNA 的间隙反义寡核苷酸(ASO)。我们合成了约 300 种针对不同 SARS-CoV-2 RNA 区域设计的间隙聚合物 ASO,并在基于细胞的试验中评估了它们的活性。通过在细胞培养系统中进行多步筛选,我们发现针对病毒主蛋白酶编码区的 ASO#41 能降低感染细胞中的 SARS-CoV-2 RNA 水平,并抑制病毒诱导的细胞病理效应。在 iPS 细胞衍生的人肺器官组织中也观察到了 ASO#41 的抗病毒作用。在基因组复制过程中,ASO#41 以内源性 RNaseH 依赖性方式消耗细胞内病毒 RNA。ASO#41 对包括 Alpha、Delta 和 Omicron 在内的 SARS-CoV-2 变体具有广泛的抗病毒活性。小鼠经鼻给药后,ASO#41 会在肺部细胞内蓄积,并显著降低病毒感染滴度,同时减轻 SARS-CoV-2 感染导致的体重减轻。通过含磷酸胍骨架连接的进一步化学修饰,提高了抗 SARS-CoV-2 的活性,50% 的抗病毒抑制浓度为 23.4 nM,是迄今报道的最强抗 SARS-CoV-2 ASO 之一。我们的研究提出了一种鉴别抗 SARS-CoV-2 活性 ASO 的方法,它可能有助于通过靶向呼吸道病毒的基因组 RNA 建立抗病毒策略。
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引用次数: 0
Import of extracellular 2′-3′cGAMP by the folate transporter, SLC19A1, establishes an antiviral response that limits herpes simplex virus-1 叶酸转运体 SLC19A1 导入细胞外 2'-3'cGAMP 可建立抗病毒反应,限制单纯疱疹病毒-1。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-21 DOI: 10.1016/j.antiviral.2024.105989
Zsuzsa K. Szemere, Eain A. Murphy

Recently it was discovered that extracellular 2′-3′cGAMP can activate the STING pathway in a cGAS-independent fashion by being transported across the cell membrane via the folate transporter, SLC19A1, the first identified extracellular antiporter of this critical signaling molecule in cancer cells. We hypothesized that this non-canonical activation of STING pathway would function to establish an antiviral state similar to that seen with the paracrine antiviral activities of interferon. Herein, we report that treatment of the monocytic cell line, THP-1 cells and SH-SY5Y neuronal cell line with exogenous 2′-3′cGAMP induces interferon production and establishes an antiviral state that limits herpes simplex virus-1 (HSV-1), a ubiquitous virus with high seropositivity in the human population. Using either pharmaceutical inhibition or genetic knockout of SLC19A1 blocks the 2′-3′cGAMP-induced inhibition of viral replication. Our data indicate SLC19A1 functions as a newly identified antiviral mediator for extracellular 2′-3′cGAMP. This work presents novel and important findings about an antiviral mechanism which information could aid in the development of better antiviral drugs in the future.

最近发现,细胞外的 2'-3'cGAMP 可通过叶酸转运体 SLC19A1 跨细胞膜转运,以一种不依赖于 cGAS 的方式激活 STING 通路。我们假设 STING 通路的这种非经典激活功能将建立一种抗病毒状态,类似于干扰素的旁分泌抗病毒活性。在此,我们报告了用外源 2'-3'cGAMP 处理单核细胞系、THP-1 细胞和 SH-SY5Y 神经元细胞系可诱导干扰素产生,并建立一种限制单纯疱疹病毒-1(HSV-1)的抗病毒状态。使用药物抑制或基因敲除 SLC19A1 可阻止 2'-3'cGAMP 诱导的病毒复制抑制。我们的数据表明,SLC19A1 是一种新发现的细胞外 2'-3'cGAMP 抗病毒介质。这项工作提供了有关抗病毒机制的新颖而重要的发现,这些信息有助于将来开发更好的抗病毒药物。
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引用次数: 0
A novel live DNA tagging system for African swine fever virus shows that bisbenzimide Hoechst 33342 can effectively block its replication 一种新型非洲猪瘟病毒活 DNA 标记系统显示,双苯亚胺 Hoechst 33342 能有效阻断非洲猪瘟病毒的复制
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-19 DOI: 10.1016/j.antiviral.2024.105973
Veronica Martin , Beatriz Guerra , Bruno Hernaez , Sandrine Kappler-Gratias , Franck Gallardo , Milagros Guerra , German Andres , Ali Alejo

African swine fever virus (ASFV) infection causes a frequently fatal disease in domestic swine that has affected more than 50 countries worldwide since 2021, with a major impact on animal welfare and economy. The development of effective vaccines or antivirals against this disease are urgently required for its effective control. Live detection of viral replication has been used as a tool for the screening and characterization of antiviral compounds in other dsDNA genome containing viruses. Here, we have adapted the ANCHOR fluorescent DNA labelling system to ASFV by constructing and characterizing a novel recombinant virus. We show that this virus is viable and effectively tags viral DNA replication sites, which can be detected and quantified in real time. Further, we have used high content cell microscopy to test the antiviral activity of bisbenzimide compounds and show that Hoechst 33342 has specific anti-ASFV activity. We expect this novel tool to be useful both in the further study of ASFV replication as in the screening of new specific antiviral compounds.

非洲猪瘟病毒(ASFV)感染导致家猪经常患上致命疾病,自 2021 年以来已波及全球 50 多个国家,对动物福利和经济造成了重大影响。为有效控制该疾病,迫切需要开发有效的疫苗或抗病毒药物。病毒复制的活体检测已被用作筛选和鉴定其他含 dsDNA 基因组病毒的抗病毒化合物的工具。在这里,我们通过构建和鉴定一种新型重组病毒,将 ANCHOR 荧光 DNA 标记系统应用于 ASFV。我们的研究表明,这种病毒具有生命力,能有效标记病毒 DNA 复制位点,并能对其进行实时检测和定量。此外,我们还利用高含量细胞显微镜检测了双苯并咪唑类化合物的抗病毒活性,结果表明 Hoechst 33342 具有特异性抗 ASFV 活性。我们希望这种新工具能在进一步研究 ASFV 复制和筛选新的特异性抗病毒化合物方面发挥作用。
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引用次数: 0
Discovery of a small-molecule inhibitor of KSHV lytic replication from the MMV pandemic response box 从 MMV 大流行反应盒中发现 KSHV 溶菌复制的小分子抑制剂。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-16 DOI: 10.1016/j.antiviral.2024.105990
Michael O. Okpara , Frederick Weaver , Adrian Whitehouse , Clinton G.L. Veale , Adrienne L. Edkins

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent for primary effusion lymphoma (PEL), multicentric Castleman's disease (MCD) and Kaposi's sarcoma (KS). KSHV is one of the oncoviruses that contribute to 1.5 million new infection-related cancer cases annually. Currently, there are no targeted therapies for KSHV-associated diseases. Through the development of a medium-throughput phenotype-based ELISA screening platform based on KSHV ORF57 protein detection, we screened the Medicines for Malaria Venture (MMV) Pandemic Response Box for non-cytotoxic inhibitors of KSHV lytic replication. MMV1645152 was identified as a promising inhibitor of KSHV lytic replication, suppressing KSHV immediate-early and late lytic gene expression and blocking the production of infectious KSHV virion particles at non-cytotoxic concentrations in cell line models of KSHV infection with or without EBV coinfection. MMV1645152 is a promising hit compound for the development of future therapeutic agents against KSHV-associated malignancies.

卡波西肉瘤相关疱疹病毒(KSHV)是原发性渗出性淋巴瘤(PEL)、多中心卡斯特曼病(MCD)和卡波西肉瘤(KS)的致病因子。KSHV 是导致每年新增 150 万例感染相关癌症病例的肿瘤病毒之一。目前,还没有针对 KSHV 相关疾病的靶向疗法。通过开发基于 KSHV ORF57 蛋白检测的中等通量表型 ELISA 筛选平台,我们在疟疾新药研发公司(MMV)大流行响应箱中筛选出了 KSHV 溶解复制的非细胞毒性抑制剂。MMV1645152 被确定为一种很有前景的 KSHV 溶菌复制抑制剂,它能抑制 KSHV 即刻-早期和晚期溶菌基因的表达,并在有或没有 EBV 共感染的 KSHV 感染细胞系模型中以非细胞毒性浓度阻断传染性 KSHV 病毒粒子的产生。MMV1645152 是一种很有希望的热门化合物,可用于开发未来针对 KSHV 相关恶性肿瘤的治疗药物。
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引用次数: 0
Comprehensive database of HIV mutations selected during antiretroviral in vitro passage experiments 抗逆转录病毒体外传代实验中选择的 HIV 变异综合数据库。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-16 DOI: 10.1016/j.antiviral.2024.105988
Kaiming Tao, Jinru Zhou, Pavithra Nagarajan, Philip L. Tzou, Robert W. Shafer

Background

In vitro passage experiments are crucial to the development of antiretroviral (ARV) drugs.

Methods

We created an online database containing data from 102 published studies in which HIV-1 or HIV-2 was cultured with increasing concentrations of the FDA-approved nucleoside RT inhibitors (NRTIs), nonnucleoside RT inhibitors (NNRTIs), integrase strand transfer inhibitors (INSTIs), protease inhibitors (PIs), capsid inhibitor (CAI) lenacapavir, and nucleoside RT translocation inhibitor (NRTTI) islatravir. We summarized the mutations selected in the subset of passage experiments with NRTIs lamivudine (3TC), emtricitabine (FTC), abacavir (ABC), tenofovir (TFV), and zidovudine (AZT), NNRTIs doravirine (DOR), efavirenz (EFV), and rilpivirine (RPV), INSTIs bictegravir (BIC), cabotegravir (CAB), and dolutegravir (DTG), and PIs atazanavir (ATV), darunavir (DRV), and lopinavir (LPV). Mutations selected in vitro were compared with those selected in persons receiving the same ARV.

Results

Twenty-seven studies described 89 experiments of wildtype isolates passaged with 3TC, FTC, ABC, TFV, or AZT; sixteen studies described 89 experiments passaged with EFV, RPV, or DOR; eleven studies described 76 experiments passaged with the INSTIs BIC, CAB, or DTG; six studies described 33 experiments passaged with ATV, LPV, or DRV. With several exceptions, mutations selected in two or more experiments were among the most common mutations selected in persons receiving the same ARV.

Conclusions

We created a database of published ARV in vitro selection experiments. Mutations emerging from these experiments generally predict those observed in persons receiving the same ARV. However, there are notable differences in mutation frequencies between in vitro and in vivo settings.

背景:体外通过实验是开发抗逆转录病毒(ARV)药物的关键:体外通过实验对于抗逆转录病毒(ARV)药物的开发至关重要:我们创建了一个在线数据库,其中包含102项已发表研究的数据,在这些研究中,HIV-1或HIV-2与FDA批准的核苷类RT抑制剂(NRTIs)、非核苷类RT抑制剂(NNRTIs)、整合酶链转移抑制剂(INSTIs)、蛋白酶抑制剂(PIs)、囊膜抑制剂(CAI)来那卡韦以及核苷类RT转位抑制剂(NRTTI)伊斯拉曲韦一起培养。我们总结了在使用 NRTIs 拉米夫定(3TC)、恩曲他滨(FTC)、阿巴卡韦(ABC)、替诺福韦(TFV)和齐多夫定(AZT)的实验中筛选出的突变、NNRTIs:多拉韦林(DOR)、依非韦伦(EFV)和利匹韦林(RPV);INSTIs:比特拉韦(BIC)、卡博替拉韦(CAB)和多罗替拉韦(DTG);PIs:阿扎那韦(ATV)、达鲁那韦(DRV)和洛匹那韦(LPV)。将体外筛选出的突变与接受相同抗逆转录病毒药物治疗的患者体内筛选出的突变进行了比较:27 项研究描述了野生型分离株与 3TC、FTC、ABC、TFV 或 AZT 一起进行的 89 次实验;16 项研究描述了与 EFV、RPV 或 DOR 一起进行的 89 次实验;11 项研究描述了与 INSTIs BIC、CAB 或 DTG 一起进行的 76 次实验;6 项研究描述了与 ATV、LPV 或 DRV 一起进行的 33 次实验。除个别情况外,在两个或多个实验中选择的突变都是在接受同一种抗逆转录病毒药物治疗的患者中最常见的突变:结论:我们建立了一个已发表的抗逆转录病毒药物体外选择实验数据库。结论:我们建立了一个已发表的抗逆转录病毒药物体外选择实验数据库。这些实验中出现的突变一般都能预测在接受相同抗逆转录病毒药物治疗的人群中观察到的突变。然而,体外和体内的突变频率存在明显差异。
{"title":"Comprehensive database of HIV mutations selected during antiretroviral in vitro passage experiments","authors":"Kaiming Tao,&nbsp;Jinru Zhou,&nbsp;Pavithra Nagarajan,&nbsp;Philip L. Tzou,&nbsp;Robert W. Shafer","doi":"10.1016/j.antiviral.2024.105988","DOIUrl":"10.1016/j.antiviral.2024.105988","url":null,"abstract":"<div><h3>Background</h3><p><em>In vitro</em> passage experiments are crucial to the development of antiretroviral (ARV) drugs.</p></div><div><h3>Methods</h3><p>We created an online database containing data from 102 published studies in which HIV-1 or HIV-2 was cultured with increasing concentrations of the FDA-approved nucleoside RT inhibitors (NRTIs), nonnucleoside RT inhibitors (NNRTIs), integrase strand transfer inhibitors (INSTIs), protease inhibitors (PIs), capsid inhibitor (CAI) lenacapavir, and nucleoside RT translocation inhibitor (NRTTI) islatravir. We summarized the mutations selected in the subset of passage experiments with NRTIs lamivudine (3TC), emtricitabine (FTC), abacavir (ABC), tenofovir (TFV), and zidovudine (AZT), NNRTIs doravirine (DOR), efavirenz (EFV), and rilpivirine (RPV), INSTIs bictegravir (BIC), cabotegravir (CAB), and dolutegravir (DTG), and PIs atazanavir (ATV), darunavir (DRV), and lopinavir (LPV). Mutations selected <em>in vitro</em> were compared with those selected in persons receiving the same ARV.</p></div><div><h3>Results</h3><p>Twenty-seven studies described 89 experiments of wildtype isolates passaged with 3TC, FTC, ABC, TFV, or AZT; sixteen studies described 89 experiments passaged with EFV, RPV, or DOR; eleven studies described 76 experiments passaged with the INSTIs BIC, CAB, or DTG; six studies described 33 experiments passaged with ATV, LPV, or DRV. With several exceptions, mutations selected in two or more experiments were among the most common mutations selected in persons receiving the same ARV.</p></div><div><h3>Conclusions</h3><p>We created a database of published ARV <em>in vitro</em> selection experiments. Mutations emerging from these experiments generally predict those observed in persons receiving the same ARV. However, there are notable differences in mutation frequencies between <em>in vitro</em> and <em>in vivo</em> settings.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0166354224001979/pdfft?md5=0b3b2fe533646d47200e5fa992150e2d&pid=1-s2.0-S0166354224001979-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Characterization of therapeutic antibody efficacy against multiple SARS-CoV-2 variants in the hamster model 在仓鼠模型中鉴定针对多种 SARS-CoV-2 变体的治疗性抗体的疗效。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-13 DOI: 10.1016/j.antiviral.2024.105987
Yu Cong , Saurabh Dixit , Donna L. Perry , Louis M. Huzella , Erin Kollins , Russell Byrum , Scott M. Anthony , David Drawbaugh , Sanae Lembirik , Elena Postnikova , Brett Eaton , Michael Murphy , Gregory Kocher , Kyra Hadley , Anthony E. Marketon , Rebecca M. Bernbaum , Amanda M.W. Hischak , Randy Hart , Nick Vaughan , Jiro Wada , Michael R. Holbrook

The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and onset of the coronavirus disease-19 (COVID-19) pandemic led to an immediate need for therapeutic treatment options. Therapeutic antibodies were developed to fill a gap when traditional antivirals were not available. In late 2020, the United States Government undertook an effort to compare candidate therapeutic antibodies in virus neutralization assays and in the hamster model of SARS-CoV-2 infection. With the emergence of SARS-CoV-2 variants, the effort expanded to evaluate the efficacy of nearly 50 products against major variants. A subset of products was further evaluated for therapeutic efficacy in hamsters. Here we report results of the hamster studies, including pathogenicity with multiple variants, neutralization capacity of products, and efficacy testing of products against Delta and Omicron variants. These studies demonstrate the loss of efficacy of early products with variant emergence and support the use of the hamster model for evaluating therapeutics.

严重急性呼吸系统综合征冠状病毒-2(SARS-CoV-2)的出现和冠状病毒病-19(COVID-19)的大流行导致了对治疗方案的迫切需求。治疗性抗体的开发填补了传统抗病毒药物的空白。2020 年末,美国政府开始在病毒中和试验和 SARS-CoV-2 仓鼠感染模型中对候选治疗抗体进行比较。随着 SARS-CoV-2 变体的出现,这项工作扩大到评估近 50 种产品对主要变体的疗效。对其中一部分产品在仓鼠中的疗效进行了进一步评估。我们在此报告仓鼠研究的结果,包括多种变异体的致病性、产品的中和能力,以及产品对 Delta 和 Omicron 变异体的疗效测试。这些研究表明,随着变异体的出现,早期产品的疗效会减弱,因此支持使用仓鼠模型来评估治疗方法。
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引用次数: 0
Mosaic neuraminidase-based vaccine induces antigen-specific T cell responses against homologous and heterologous influenza viruses 基于马赛克神经氨酸酶的疫苗可诱导抗原特异性 T 细胞对同源和异源流感病毒产生反应。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-06 DOI: 10.1016/j.antiviral.2024.105978
Zirong Han , Qianyi Mai , Yangguo Zhao , Xinglai Liu , Mingting Cui , Minchao Li , Yaoqing Chen , Yuelong Shu , Jianhui Gan , Weiqi Pan , Caijun Sun

Seasonal influenza is an annually severe crisis for global public health, and an ideal influenza vaccine is expected to provide broad protection against constantly drifted strains. Compared to highly flexible hemagglutinin (HA), increasing data have demonstrated that neuraminidase (NA) might be a potential target against influenza variants. In the present study, a series of genetic algorithm-based mosaic NA were designed, and then cloned into recombinant DNA and replication-defective Vesicular Stomatitis Virus (VSV) vector as a novel influenza vaccine candidate. Our Results showed that DNA prime/VSV boost strategy elicited a robust NA-specific Th1-dominated immune response, but the traditional inactivated influenza vaccine elicited a Th2-dominated immune response. More importantly, the superior NA-specific immunity induced by our strategy could confer both a full protection against lethal homologous influenza challenge and a partial protection against heterologous influenza infection. These findings will provide insights on designing NA-based universal vaccine strategy against influenza variants.

季节性流感每年都会给全球公共卫生带来严重危机,理想的流感疫苗应能针对不断变异的毒株提供广泛的保护。与高度灵活的血凝素(HA)相比,越来越多的数据表明神经氨酸酶(NA)可能是对抗流感变异株的潜在靶标。在本研究中,我们设计了一系列基于遗传算法的镶嵌 NA,然后将其克隆到重组 DNA 和复制缺陷水泡性口炎病毒(VSV)载体中,作为新型流感疫苗的候选株。我们的研究结果表明,DNA质粒/VSV增强策略能激发以Th1为主的强NA特异性免疫反应,而传统的灭活流感疫苗则能激发以Th2为主的免疫反应。更重要的是,我们的策略所诱导的超强NA特异性免疫既能对致命的同源流感挑战提供全面保护,也能对异源流感感染提供部分保护。这些发现将为设计以NA为基础的通用疫苗策略来对抗流感变种提供启示。
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引用次数: 0
Amidino-rocaglates (ADRs), a class of synthetic rocaglates, are potent inhibitors of SARS-CoV-2 replication through inhibition of viral protein synthesis 脒基洛卡酸盐(ADRs)是一类合成洛卡酸盐,通过抑制病毒蛋白质的合成,对 SARS-CoV-2 的复制有很强的抑制作用。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-06 DOI: 10.1016/j.antiviral.2024.105976
Patrick T. Keiser , Wenhan Zhang , Michael Ricca , Alan Wacquiez , Autumn Grimins , Regina Cencic , J.J. Patten , Pranav Shah , Elias Padilha , John H. Connor , Jerry Pelletier , Shawn M. Lyons , Mohsan Saeed , Lauren E. Brown , John A. Porco Jr. , Robert A. Davey

Coronaviruses are highly transmissible respiratory viruses that cause symptoms ranging from mild congestion to severe respiratory distress. The recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has underscored the need for new antivirals with broad-acting mechanisms to combat increasing emergence of new variants. Currently, there are only a few antivirals approved for treatment of SARS-CoV-2. Previously, the rocaglate natural product silvestrol and synthetic rocaglates such as CR-1-31b were shown to have antiviral effects by inhibiting eukaryotic translation initiation factor 4A1 (eIF4A) function and virus protein synthesis. In this study, we evaluated amidino-rocaglates (ADRs), a class of synthetic rocaglates with the most potent eIF4A-inhibitory activity to-date, for inhibition of SARS-CoV-2 infection. This class of compounds showed low nanomolar potency against multiple SARS-CoV-2 variants and in multiple cell types, including human lung-derived cells, with strong inhibition of virus over host protein synthesis and low cytotoxicity. The most potent ADRs were also shown to be active against two highly pathogenic and distantly related coronaviruses, SARS-CoV and MERS-CoV. Mechanistically, cells with mutations of eIF4A1, which are known to reduce rocaglate interaction displayed reduced ADR-associated loss of cellular function, consistent with targeting of protein synthesis. Overall, ADRs and derivatives may offer new potential treatments for SARS-CoV-2 with the goal of developing a broad-acting anti-coronavirus agent.

冠状病毒是一种传播性极强的呼吸道病毒,可引起从轻微充血到严重呼吸困难的各种症状。最近爆发的严重急性呼吸系统综合征冠状病毒 2(SARS-CoV-2)突出表明,需要具有广谱作用机制的新型抗病毒药物来应对日益增多的新变种。目前,只有少数抗病毒药物被批准用于治疗 SARS-CoV-2 。在此之前,rocaglate 天然产物 silvestrol 和合成的 rocaglates(如 CR-1-31b)通过抑制真核翻译起始因子 4A1(eIF4A)的功能和病毒蛋白质的合成而被证明具有抗病毒作用。在本研究中,我们评估了脒基环烷酸酯(ADRs)对 SARS-CoV-2 感染的抑制作用,这是迄今为止具有最强 eIF4A 抑制活性的一类合成环烷酸酯。这类化合物对多种 SARS-CoV-2 变体和多种细胞类型(包括人肺源性细胞)都显示出低纳摩尔的效力,对病毒和宿主蛋白质合成的抑制作用强,细胞毒性低。最有效的 ADRs 对两种高致病性和远缘冠状病毒(SARS-CoV 和 MERS-CoV)也具有活性。从机理上讲,已知 eIF4A1 基因突变会减少罗卡格雷特的相互作用,而 eIF4A1 基因突变的细胞会减少 ADR 导致的细胞功能丧失,这与蛋白质合成的靶向性是一致的。总之,ADR及其衍生物可能为SARS-CoV-2提供新的潜在治疗方法,从而达到开发广谱抗冠状病毒药物的目的。
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引用次数: 0
Synergistic activity of an RNA polymerase PA-PB1 interaction inhibitor with oseltamivir against human and avian influenza viruses in cell culture and in ovo 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 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

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.

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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引用次数: 0
Orally dissolving film as a potential vaccine delivery carrier to prevent influenza virus infection 将口腔溶解膜作为预防流感病毒感染的潜在疫苗输送载体。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-05 DOI: 10.1016/j.antiviral.2024.105979
Keon-Woong Yoon , Ki Back Chu , Gi-Deok Eom , Jie Mao , Sung Soo Kim , Fu-Shi Quan

Orally dissolving films (ODF) are designed to be dissolved on the tongue and absorbed in the mouth. It offers multiple advantages over the commonly used needle-based vaccines, especially in terms of convenience allowing safe, painless, and easy self-administration. As the efficacy of ODF-encapsulated influenza vaccines has not been demonstrated, we assessed the protection elicited by inactivated influenza virus (A/PR/8/34, PR8) vaccine delivered using ODFs in mice. Trehalose and pullulan components of the ODF ensured that the HA antigens of the inactivated PR8 virus retained their stability while ensuring the rapid release of the vaccines upon exposure to murine saliva. Mice were immunized thrice by placing the PR8-ODF on the tongues of mice at 4-week intervals, and vaccine-induced protection was evaluated upon lethal homologous challenge infection. The PR8-ODF vaccination elicited virus-specific serum IgG and IgA antibody responses, hemagglutinin inhibition (HAI), and viral neutralization. Upon challenge infection, ODF vaccination showed higher levels of IgG and IgA antibody responses in the lungs and antibody-secreting cell (ASC) responses in both lung and spleen compared to unimmunized controls. These results corresponded with the enhanced T cell and germinal center B cell responses in the lungs and spleens. Importantly, ODF vaccination significantly reduced lung virus titers and inflammatory cytokines (IFN-γ, IL-6) production compared to unvaccinated control. ODF vaccination ensured 100% survival and prevented weight loss in mice. These findings suggest that influenza vaccine delivery through ODFs could be a promising approach for oral vaccine development.

口腔溶解膜(ODF)可在舌头上溶解并在口腔中吸收。与常用的针剂疫苗相比,口服溶解膜疫苗具有多种优势,尤其是在安全、无痛、简便的自我注射方面。由于 ODF 封装流感疫苗的功效尚未得到证实,我们评估了使用 ODF 给小鼠注射灭活流感病毒(A/PR/8/34,PR8)疫苗所产生的保护作用。ODF 中的海藻糖和纤维素成分可确保灭活的 PR8 病毒的 HA 抗原保持稳定,同时确保疫苗在暴露于小鼠唾液后迅速释放。每隔 4 周将 PR8-ODF 放在小鼠舌头上,对小鼠进行三次免疫接种,并在致死性同源挑战感染时评估疫苗诱导的保护作用。接种PR8-ODF疫苗可引起病毒特异性血清IgG和IgA抗体反应、血凝素抑制(HAI)和病毒中和。与未接种疫苗的对照组相比,接种 ODF 疫苗后在肺部出现更高水平的 IgG 和 IgA 抗体反应,在肺部和脾脏出现更高水平的抗体分泌细胞 (ASC) 反应。这些结果与肺部和脾脏中增强的 T 细胞和生殖中心 B 细胞反应相吻合。重要的是,与未接种疫苗的对照组相比,接种ODF可显著降低肺部病毒滴度和炎性细胞因子(IFN-γ、IL-6)的产生。接种ODF疫苗可确保小鼠100%存活并防止体重减轻。这些研究结果表明,通过ODF输送流感疫苗是一种很有前景的口服疫苗开发方法。
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