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An Oleanolic Acid Derivative Inhibits Hemagglutinin-Mediated Entry of Influenza A Virus.

一种齐墩果酸衍生物抑制血凝素介导的甲型流感病毒进入。

  • 影响因子:4.03
  • DOI:10.3390/v12020225
  • 作者列表:"Ye M","Liao Y","Wu L","Qi W","Choudhry N","Liu Y","Chen W","Song G","Chen J
  • 发表时间:2020-02-18
Abstract

:Influenza A viruses (IAV) have been a major public health threat worldwide, and options for antiviral therapy become increasingly limited with the emergence of drug-resisting virus strains. New and effective anti-IAV drugs, especially for highly pathogenic influenza, with different modes of action, are urgently needed. The influenza virus glycoprotein hemagglutinin (HA) plays critical roles in the early stage of virus infection, including receptor binding and membrane fusion, making it a potential target for the development of anti-influenza drugs. In this study, we show that OA-10, a newly synthesized triterpene out of 11 oleanane-type derivatives, exhibited significant antiviral activity against four different subtypes of IAV (H1N1, H5N1, H9N2 and H3N2) replications in A549 cell cultures with EC50 ranging from 6.7 to 19.6 μM and a negligible cytotoxicity (CC50 > 640 μM). It inhibited acid-induced hemolysis in a dose-dependent manner, with an IC50 of 26 µM, and had a weak inhibition on the adsorption of H5 HA to chicken erythrocytes at higher concentrations (≥40 µM). Surface plasmon resonance (SPR) analysis showed that OA-10 interacted with HA in a dose-dependent manner with the equilibrium dissociation constants (KD) of the interaction of 2.98 × 10-12 M. Computer-aided molecular docking analysis suggested that OA-10 might bind to the cavity in HA stem region which is known to undergo significant rearrangement during membrane fusion. Our results demonstrate that OA-10 inhibits H5N1 IAV replication mainly by blocking the conformational changes of HA2 subunit required for virus fusion with endosomal membrane. These findings suggest that OA-10 could serve as a lead for further development of novel virus entry inhibitors to prevent and treat IAV infections.

摘要

甲型流感病毒 (Influenza A virus es,IAV) 一直是全球范围内的主要公共卫生威胁,随着药物抵抗病毒株的出现,抗病毒治疗的选择越来越有限。迫切需要新的有效的抗 IAV 药物,尤其是针对高致病性流感,具有不同作用方式的药物。流感病毒糖蛋白血凝素 (HA) 在病毒感染的早期阶段起着关键作用,包括受体结合和膜融合,使其成为抗流感药物开发的潜在靶点。在这项研究中,我们发现 OA-10 是一种新合成的三萜类化合物,由 11 个齐墩果烷型衍生物组成,对 IAV 的四种不同亚型 (H1N1 、 H5N1 、 H9N2 和 H3N2) 表现出显著的抗病毒活性 a549 细胞培养物中的重复,EC50 范围为 6.7-19.6 μ m,细胞毒性可忽略不计 (CC50> 640 μ m)。它以剂量依赖性方式抑制酸诱导的溶血,IC50 为 26 µ m, 在较高浓度 (≥ 40 µ m) 时,对 H5 HA 对鸡红细胞的吸附有较弱的抑制作用。表面等离子体共振 (SPR) 分析表明,OA-10 与 HA 的相互作用呈剂量依赖性,其相互作用的平衡解离常数 (KD) 为 2.98 × 10-12 M。计算机辅助分子对接分析表明,OA-10 可能与已知在膜融合过程中发生显著重排的 HA 茎区域的空腔结合。我们的结果表明,OA-10 主要通过阻断病毒与内体膜融合所需的 HA2 亚基的构象变化来抑制 H5N1 IAV 复制。这些发现表明,OA-10 可以作为进一步开发新型病毒进入抑制剂的先导,以预防和治疗 IAV 感染。

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发表时间:2020-01-19
DOI:10.1093/cid/ciaa050
作者列表:["Baum U","Kulathinal S","Auranen K","Nohynek H"]

METHODS:BACKGROUND:From 2015/16 through 2017/18, injectable, trivalent inactivated influenza vaccines (IIV3) and a nasal spray, tetravalent live-attenuated influenza vaccine (LAIV4) were used in parallel in Finland. To understand how well vaccination with each vaccine type protected children against influenza under real-life conditions, vaccine effectiveness in two-year-olds was estimated for all three seasons. METHODS:Each season, a nationwide register-based cohort study was conducted. The study population comprised 60,088 children in 2015/16, 60,860 children in 2016/17 and 60,345 children in 2017/18. Laboratory-confirmed influenza was the study outcome. Seasonal influenza vaccination with either LAIV4 or IIV3 was the time-dependent exposure of interest. Vaccine effectiveness was defined as 1 minus the hazard ratio comparing vaccinated with unvaccinated children. RESULTS:From 2015/16 through 2017/18, the effectiveness of LAIV4 against influenza of any virus type was estimated at 54.2% (95% confidence interval, 32.2%-69.0%), 20.3% (-12.7% to 43.6%) and 30.5% (10.9%-45.9%); the corresponding effectiveness of IIV3 was 77.2% (48.9%-89.8%), 24.5% (-29.8% to 56.1%) and -20.1% (-61.5% to 10.7%). Neither of the influenza vaccines clearly excelled in protecting children. The LAIV4 effectiveness against type B was greater than against type A and greater than the IIV3 effectiveness against type B. CONCLUSIONS:To understand how influenza vaccines could be improved, vaccine effectiveness must be analyzed by vaccine and virus type. Effectiveness estimates expressing also overall protection levels are needed to guide individual and programmatic decision-making processes. Supported by this analysis, the vaccination program in Finland now recommends LAIV4 and injectable, tetravalent inactivated influenza vaccines replacing IIV3.

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影响因子:1.36
发表时间:2020-01-20
DOI:10.1111/1348-0421.12775
作者列表:["Ainai A","van Riet E","Ito R","Ikeda K","Senchi K","Suzuki T","Tamura SI","Asanuma H","Odagiri T","Tashiro M","Kurata T","Multihartina P","Setiawaty V","Andriana Pangesti KN","Hasegawa H"]

METHODS::Intranasally administered influenza vaccines could be more effective than injected vaccines, since intranasal vaccination can induce virus-specific IgA antibodies in the upper respiratory tract, which is the initial site of infection. In the current study, immune responses elicited by an intranasal inactivated H5 influenza vaccine were evaluated in healthy H5 influenza virus-naive individuals. Three doses of intranasal inactivated whole-virion H5 influenza vaccine induced strong neutralizing nasal IgA and serum IgG antibodies. In addition, a mucoadhesive excipient, carboxy-vinyl polymer (CVP), had a notable impact on the induction of nasal IgA antibody responses but not serum IgG antibody responses. The nasal hemagglutinin (HA)-specific IgA antibody responses clearly correlated with mucosal neutralizing antibody responses, indicating that measurement of nasal HA-specific IgA titers could be used as a surrogate for the mucosal antibody response. Furthermore, increased numbers of plasma cells and vaccine antigen-specific helper T (Th) cells in the peripheral blood were observed after vaccination, suggesting that peripheral blood biomarkers may also be used to evaluate the intranasal vaccine-induced immune response. However, peripheral blood immune cell responses correlated with neutralizing antibody titers in serum samples but not in nasal wash samples. Thus, analysis of the peripheral blood immune response could be a surrogate for the systemic immune response to intranasal vaccination but not for the mucosal immune response. The current study suggests the clinical potential of intranasal inactivated vaccines against H5 influenza viruses and highlights the need to develop novel means to evaluate intranasal vaccine-induced mucosal immune responses. This article is protected by copyright. All rights reserved.

影响因子:6.53
发表时间:2020-01-21
DOI:10.1016/S1473-3099(19)30584-5
作者列表:["Liebowitz D","Gottlieb K","Kolhatkar NS","Garg SJ","Asher JM","Nazareno J","Kim K","McIIwain DR","Tucker SN"]

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