Identification and characterization of the human factors targeted by the Nucleic Acid Polymers (NAP) responsible for its antiviral activity against HBV and HDV.

核酸聚合物（NAP）针对 HBV 和 HDV 抗病毒活性的人为因素的鉴定和表征。

• 批准号: 558342-2020
• 负责人: Labonté, PatrickP
• 金额: $ 3.33万
• 依托单位: Institut national de la recherche scientifique
• 依托单位国家: 加拿大
• 项目类别: Alliance Grants
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=757489
• 关键词: Identification; characterization; human; factors; targeted

Chronic infection by the hepatitis B virus (HBV) is a major etiologic factor in the development of severe liver diseases including fibrosis, cirrhosis and hepatocellular carcinoma. Over 290 million people worldwide and 54 000 Canadians are chronically infected with HBV and, at the moment, no cure has been discovered. In addition, when HBV infection is accompanied by coinfection with the hepatitis delta virus (HDV), a satellite virus of HBV, acceleration of the liver diseases progression is common. While currently approved therapies for HBV are used in coinfected patients in an attempt to limit liver disease progression they are only minimally effective in achieving this goal. Importantly, functional cure of HBV (where HBV viremia remains undetectable in the blood and liver function remains normal after removal of therapy), and similar control of HDV infection in coinfected patients has been observed lately with a new class of antiviral molecules named nucleic acid polymers (NAPs) when used in combination with existing approved therapies for HBV infection. However, the development and commercialization of NAPs is hampered by a lack of understanding of their mechanism-of-action. Therefore, this proposal is aimed at defining how this new class of molecules exert their antiviral effects during HBV infection as well as during coinfection with its satellite virus, HDV. In aim 1, we will characterize how NAPs selectively inhibit the assembly/secretion of HBV subviral particles without affecting the morphogenesis and secretion of infectious Dane particles. In aim 2, an in-depth analysis of the mechanism-of-action of NAPs on the HDV replication-cycle will be performed.

乙型肝炎病毒（HBV）慢性感染是严重肝脏疾病（包括纤维化，肝硬化和肝细胞癌）发展的主要病因。全球超过2.9亿人，5.4 000名加拿大人长期感染了HBV，目前尚未发现治愈。另外，当HBV感染与HBV的卫星病毒伴有Delta病毒（HDV）的共同感染时，肝脏疾病进展的加速度很常见。尽管目前已批准的HBV疗法用于共同感染的患者，以试图限制肝脏疾病进展，但仅在实现这一目标方面至少有效。重要的是，HBV的功能治愈（去除治疗后血液和肝功能中的HBV病毒血症在血液和肝功能中仍然无法检测到），并且在与现有批准的The Infction合并时，已观察到与新的抗病毒药物分子（NAPS）相似的相似的HDV感染对共感染患者的HDV感染相似。但是，由于缺乏对行动机制的了解，午睡的发展和商业化受到阻碍。因此，该建议旨在定义这种新的分子在HBV感染期间以及与其卫星病毒HDV共同感染期间如何发挥其抗病毒作用。在AIM 1中，我们将表征NAPS如何选择性地抑制HBV次病颗粒的组装/分泌，而不会影响感染性丹麦颗粒的形态发生和分泌。在AIM 2中，将对HDV复制周期上的小NAP的行动机理进行深入分析。