基于病毒包膜蛋白时空动态修饰的病毒-细胞融合研究及化学干预、靶点发现和转化

A variety of viral infections and related infectious diseases originate from virus-host fusions, which are usually accomplished by viral envelope proteins via a series of complex conformational changes and an unresolved dynamic pathway. Based on the early discovery of certain of triterpenoid natural products as broad-spectrum anti-virus entry inhibitors and precise modifications of viral vectors using unnatural amino acids as well as the generation of live replication-incompetent viruses, this proposal takes advantage of the role of the chemical approach in precise modification of the viral envelope protein to explore the fusion of influenza virus and Ebola pseudovirus, as a proof-of-concept, with their host cells and thus integrate chemistry into virology and drug discovery as a new subject. It will be divided into three directions. First at the molecular level, we try to clarify the conformation changes of the viral envelope proteins in the dynamic processes of virus-cell fusion, reveal the corresponding biological effects and get small molecules for dynamic and targeted intervention. Secondly at the cellular level, we will explore the dynamic properties of envelope conformation changes and their significant roles during viral infection by chemically and precisely temporal, spatial intervention of virus infection, and identifying the targeting sites and chemical tools for detection. Last at the animal level, we will provide scientific methods and foresights and technology prospects, via identification of potential new targets, small molecule leads and integration-incompetent live virus vaccines, for prevention and treatment of viral infectious diseases. So as to lay a foundation for the formation of new discipline growth point, bringing up multidisciplinary depth fusion and international research team of chemical biology. This will eventually lay the foundation for new disciplines, the depth of multi-disciplinary integration, and a research team with international influence and reputation, leading the discipline of chemical biology in China further forward.

病毒-细胞融合是引发病毒感染进而多种传染病的源头，通常由病毒包膜蛋白经过系列复杂构象变化和动态通路来完成。本课题基于前期发现的广谱抑制病毒进入细胞的五环三萜天然物、病毒载体非天然氨基酸精准修饰方法及复制缺陷型活病毒疫苗制备，以流感、埃博拉和HIV假病毒等为概念模式，发挥化学在病毒学和药学交叉研究中的主动优势，探索病毒包膜蛋白时空特异精准修饰的方法和干预机制。我们将在分子层面阐明病毒包膜蛋白在细胞融合过程中的动态构象和生物学效应，并实现其动态修饰的小分子靶向干预。在细胞层面发现病毒感染时空特异的化学干预方法，探索包膜蛋白的动态属性及在感染过程中发挥的作用以及动态修饰的特异标记和检测。在整体层面为药物研发提供潜在干预小分子、新靶标以及具有整合功能缺陷的活病毒疫苗，为病毒性传染病的预防和治疗提供基础性、前瞻性的方法和科学储备，并促进多学科深度融合、新学科生长及具有国际影响力的化学生物学团队建立。

病毒-细胞融合是引发病毒感染进而多种传染病的源头，通常由病毒包膜蛋白经过系列复杂构象变化和动态通路来完成。该项目在实施过程中发挥化学在病毒学和药学交叉研究中的主动优势，通过非天然氨基酸/唾液酸/天然小分子定点修饰建立的方法，探索病毒包膜蛋白时空特异精准修饰的方法和干预机制，为在分子、细胞、整体三个层面阐明病毒包膜蛋白在细胞融合过程中的动态构象变化和生物学效应，开展对病毒-细胞融合及包膜生物大分子动态修饰及化学干预研究取得了阶段性成果，包括：1. 建立了基于基因密码子扩展的在体蛋白质定点修饰方法；2. 发展了非天然氨基酸定点修饰生物大分子药物的新策略；3. 丰富了非天然氨基酸定点修饰病毒载体的新理论；4.在复制缺陷型活病毒疫苗研究领域取得了突破；5. 建立了化学干预病毒进入细胞的天然药物研究方法。