Characterization of the post-entry anti-HBV properties of nucleic acid polymers

核酸聚合物进入后抗乙肝病毒特性的表征

• 批准号: 508186-2016
• 负责人: Labonté, Patrick
• 金额: $ 5.44万
• 依托单位: Institut national de la recherche scientifique
• 依托单位国家: 加拿大
• 项目类别: Collaborative Research and Development Grants
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=619103
• 关键词: Characterization; post; entry; anti; HBV

Several polymers have been studied for their broad spectrum antiviral activity. These antiviral polymers such as polyvinyl alcohol sulfate (PVAS), sulfated polysaccharides (SPS) and polynapthalene sulfate (PNS) are believed to act primarily through inhibition of viral entry. Their antiviral activities were shown to correlate with their amphipathic character and to be length dependent and were shown to act by blocking virus-cell interaction or fusion. Recently, a new type of antiviral polymer, derived from modified nucleic acids and called nucleic acid polymers (NAPs), has also been shown to have potent, broad spectrum antiviral activity.Although the antiviral activity of NAPs in most viruses is confined to blocking viral entry and or fusion, an additional post-entry antiviral effect has been observed specifically in the case of Hepatitis B Virus (HBV) infection. This post entry activity is of important therapeutic potential as it is correlated with the elimination of serum HBV surface antigen (HBsAg), a critical event always observed in patients achieving control of their infection after antiviral therapy is stopped. Due to their good safety profile, the anti-HBV activity of NAPs has been evaluated in three proof-of-concept phase II clinical trials in patients from Bangladesh and Moldova by Replicor Inc (Montréal, Canada). When used in conjunction with a conventional immunotherapy (pegylated-interferon-alpha2a), the serum level of HBsAg declined by several logs in all patients. Such reduction in HBsAg is rarely seen in patients treated with any of the currently approved therapies for HBV infection. Due to the chronic nature of the HBV infection, the post-entry antiviral effect of NAPs is thought to be responsible for the profound reduction in HBsAg observed in treated patients. Therefore a better mechanistic understanding of the post-entry anti-HBV effects of NAPs would be beneficial to uncover the molecular machinery involved in these effects as they promise to reveal previously unknown biology in the replication cycle of HBV. Here I present a strategy for the investigation of the mechanism of action of NAPs in vitro in HBV expressing cells.

已经研究了几种聚合物的广谱抗病毒活性。这些抗病毒聚合物如聚乙烯醇硫酸酯（PVAS）、硫酸多糖（SPS）和聚萘硫酸酯（PNS）被认为主要通过抑制病毒进入而起作用。它们的抗病毒活性显示与它们的两亲性特征相关并且是长度依赖性的，并且显示通过阻断病毒-细胞相互作用或融合起作用。近年来，一种新型的抗病毒聚合物--核酸聚合物（nucleic acid polymers，NAPs）也被证明具有广谱的抗病毒活性，虽然NAPs在大多数病毒中的抗病毒活性仅限于阻断病毒进入和/或融合，但在B型肝炎病毒（Hepatitis B Virus，HBV）感染的情况下，已经观察到了额外的进入后抗病毒作用。这种入组后活性具有重要的治疗潜力，因为它与血清HBV表面抗原（HBsAg）的消除相关，这是在停止抗病毒治疗后达到感染控制的患者中经常观察到的关键事件。由于其良好的安全性，NAP的抗HBV活性已在来自孟加拉国和摩尔多瓦的患者中由Replicor Inc（加拿大蒙特利尔）进行的三项概念验证II期临床试验中进行了评估。当与常规免疫疗法（聚乙二醇化干扰素-α 2a）联合使用时，所有患者的HBsAg血清水平下降了几个对数。在接受任何目前批准的HBV感染治疗的患者中，很少见到HBsAg的这种降低。由于乙型肝炎病毒感染的慢性性质，人们认为NAP的入组后抗病毒作用是导致治疗患者中观察到的乙型肝炎表面抗原大幅降低的原因。因此，更好地理解NAP的进入后抗HBV作用的机制将有利于揭示参与这些作用的分子机制，因为它们有望揭示HBV复制周期中以前未知的生物学。在这里，我提出了一种在体外研究NAP在HBV表达细胞中的作用机制的策略。