Structural biology of the hepatitis B virus: from assembly towards design of therapeutics

乙型肝炎病毒的结构生物学：从组装到治疗设计

• 批准号: 394455587
• 负责人: Professorin Dr. Anne Schütz
• 金额: --
• 依托单位: Department Chemie
• 依托单位国家: 德国
• 项目类别: Independent Junior Research Groups
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/394455587?language=en
• 关键词: Structural; biology; hepatitis; virus; assembly

Despite the availability of a vaccine, a third of the world population has been infected with hepatitis B during their lifetime and more than 240 million people have developed a chronic infection, leaving them at high risk of developing hepatocellular carcinoma, cirrhosis and liver failure. Available drugs cannot clear the virus and escape mutations pose challenges to vaccination. A diversification of antiviral strategies is desirable targeting both virus entry and replication, in particular capsid assembly and envelopment, as well as host cell factors that sustain the virus. A prerequisite for the rational design of therapeutics is a detailed structural framework of all viral components. Despite extensive characterization of the hepatitis B virion, no unifying concept exists how the envelope, the capsid and the genome interact and assemble to yield functional viral particles at the atomic scale. One obstacle in the structural biology of this virus is its intrinsic heterogeneity, transient interactions, and dynamics, which are potentially relevant for function. We will employ nuclear magnetic resonance techniques jointly in solution and the immobilized state to monitor envelope and capsid proteins, nucleic acids and drug molecules, localizing sites of interaction and establishing how such interactions trigger structural and dynamical changes throughout the virions. In particular, our key research interests will be to rationalize the structural organization of the envelope proteins and their attachment to the capsid, to determine the structure of major surface epitope – the basis of the Hepatitis B vaccine – and to characterize the conformational and spatial dynamics of flexible segments as well as the packaging of the viral genome within the capsid. The long-term goal of this project will be to derive a structural model of the complete virion during all stages of the viral life cycle, uniting data from crystallography and cryo electron microscopy with insight into dynamics and interactions from magnetic resonance. Such a model will not only allow to rationalize virion maturation but also to predict potential interventions disturbing assembly and breaking signaling networks, which will enable the rational design of molecules that interfere with the viral life cycle for hepatitis B prevention and therapy. We will collaborate with virologists and researching medical scientists in order to maximize the translational impact of the project.

尽管有疫苗，但世界上三分之一的人口在其一生中感染过乙型肝炎，超过 2.4 亿人发展为慢性感染，使他们面临患肝细胞癌、肝硬化和肝衰竭的高风险。现有药物无法清除病毒，并且逃避突变对疫苗接种构成挑战。抗病毒策略的多样化需要针对病毒进入和复制，特别是衣壳组装和包膜，以及维持病毒的宿主细胞因子。合理设计疗法的先决条件是所有病毒成分的详细结构框架。尽管对乙型肝炎病毒颗粒进行了广泛的表征，但对于包膜、衣壳和基因组如何相互作用和组装以产生原子尺度的功能性病毒颗粒，尚不存在统一的概念。 这种病毒结构生物学的一个障碍是其内在的异质性、短暂的相互作用和动力学，这些可能与功能相关。我们将在溶液和固定状态下联合使用核磁共振技术来监测包膜蛋白和衣壳蛋白、核酸和药物分子，定位相互作用位点并确定这种相互作用如何触发整个病毒体的结构和动力学变化。特别是，我们的主要研究兴趣将是合理化包膜蛋白的结构组织及其与衣壳的附着，确定主要表面表位（乙型肝炎疫苗的基础）的结构，并表征柔性片段的构象和空间动力学以及衣壳内病毒基因组的包装。该项目的长期目标是，将晶体学和冷冻电子显微镜的数据与磁共振对动力学和相互作用的洞察结合起来，得出病毒生命周期所有阶段的完整病毒粒子的结构模型。这样的模型不仅可以使病毒粒子的成熟合理化，还​​可以预测干扰组装和破坏信号网络的潜在干预措施，这将有助于合理设计干扰病毒生命周期的分子，以预防和治疗乙型肝炎。我们将与病毒学家和研究医学科学家合作，以最大限度地发挥该项目的转化影响。