鼻咽癌是我国华南地区高发肿瘤，几乎所有鼻咽癌都与Epstein–Barr virus (EBV)感染相关。Latent membrane protein 1 (LMP-1)是EBV重要的病毒编码癌蛋白，在肿瘤细胞转化和永生过程作用至关重要。前期工作发现LMP-1的第五跨膜结构域(transmembrane domain 5，TMD-5)介导LMP-1三聚化，起始LMP-1信号，因此，LMP-1 TMD-5是开发治疗EBV诱导鼻咽癌的药物靶点。本项目利用药物化学结构-活性研究和Rosetta虚拟设计等方法发现抑制TMD-5寡聚化的分子探针；阐述其与TMD-5的分子识别模式； 通过鼻咽癌细胞和异种移植动物模型，评价TMD-5抑制剂治疗EBV诱导的鼻咽癌的效果。本项目将为调节膜域蛋白-蛋白侧向相互作用提供分子探针，发现的TMD-5抑制剂将为EBV诱导的鼻咽癌提供可能的治疗药物，因而具有重要意义。

Nasopharyngeal carcinoma (NPC) is an extremely common malignant cancer in southern regions of China and almost all NPC are associated with Epstein-Barr virus （EBV）infection. Latent membrane protein 1 (LMP-1) is the main oncogenic protein of EBV and is essential for EBV-induced cell transformation and immortalization. Therefore, LMP-1 is a molecular target for treating EBV induced NPC. Unlike the classical integral membrane receptor proteins, LMP-1 has no ligand binding site on the extracellular domain and LMP-1 signaling is constitutively activated by receptor homo-oligomerization. Owing to the lack of hot-spot, it is unlikely to target the extracellular domain of LMP-1 for drug discovery. Recently, the fifth transmembrane domain (TMD-5) of LMP-1 has been identified to mediate LMP-1 oligomerization and signaling. Therefore, targeting TMD-5 could be a good strategy to inhibit LMP-1 homo-oligomerization and signaling activation and to treat EBV induced NPC. In this project, TMD-5 inhibitors will be developed by the combination of structure-activity relationship (SAR) medicinal chemistry and Rosetta computation design. To better understand how molecular probe interrogating the protein-protein lateral interactions in cellular membranes, the binding modes of TMD-5 inhibitor with LMP-1 will be dissected by 1H-15N heteronuclear single quantum coherence (HSQC). The effects of TMD-5 inhibitors on LMP-1 signaling and the EBV induced NPC cells survival will be further evaluated. Human NPC xenografts in a nude mice model will be used to test the effects of TMD-5 inhibitor as the therapeutic for treating for treating EBV induced NPC. In summary, this project will provide molecule probes for dissecting the transmembrane protein–protein interactions. The TMD-5 inhibitors could be potential therapeutics for treating EBV induced NPC.