多种化学生物学过程协同改造病毒对肿瘤细胞的靶向性

病毒的寄生复制特性可以被巧妙地应用于肿瘤治疗，这为攻克癌症带来了新的希望，但其先决条件之一是要使病毒具有对肿瘤细胞的特异靶向性，并确保理想的感染活性。通过温和、可靠、高效的方法在病毒表面构建靶向配体，是达到这一目标的有效策略。本项目拟将化学合成和衍生方法的优势与自然的生物过程有机结合起来，构建肿瘤细胞靶向的病毒。利用细胞内胆碱磷脂的生物合成和代谢嵌入，以及病毒在复制时从宿主细胞获取包膜的机制，将化学合成的不同结构和性质的叠氮胆碱引入痘苗病毒包膜，继而通过无铜催化点击化学反应与二苯并环辛炔基衍生的叶酸或抗体偶联，构建具有高度肿瘤靶向性的痘苗病毒，同时确保较强的感染复制活性，并探索促使细胞内生物合成、代谢嵌入、病毒复制、靶向功能化等多种复杂化学生物学过程协同进行的规律，充分发挥化学生物学方法的优势，建立自然地加工和改造病毒的普适性方法，实现单纯通过化学或生物学方法难以达到的对病毒的高效改造。

The oncolytic viruses are hopefully used for tumor therapy due to their prominent antitumor efficiency and infrequent side-effects. But one of the preconditions for oncolytic virotherapy is to ensure the specific targeting of virus for tumor cells and to preserve perfect infectivity. One promising strategy for this purpose is to display ligands for cancer-associated cell surface receptors by mild, reliable and highly efficient methods. In this project, by combining the advantages of chemosynthesis methods and natural biological processes together a tumor cell-targeting virus will be constructed. The innate biosynthesis and metabolic incorporation of the choline lipids in cells will be exploited to produce the azide-functionalized membranes of cells using chemosynthesized azide-derived cholines with different structures and characteristics as substrates. Subsequently, the azide will be introduced into the envelope of vaccinia virus when it is replicated in its host cells with the azide-functionalized membranes since its envelope results from the membranes of its host cells. Then, the resulting virus will be conjugated with the dibenzocyclooctynes-derived folic acid or antibody to construct the oncolytic vaccinia virus with both high capability for targeting tumor cells and strong infectivity. We will explore the regularity about how to couple multiple complex chemical and biological processes, e.g. intrinsic biosynthesis, metabolic incorporation, replication and functionalization of the virus and so on. Hopefully, universal methods for naturally remodeling viruses with high efficiency will be established by chemical biology, which is difficult just by chemical or biological methods only.