CD147-HAb18复合物结构解析及其相关抗肝癌转移小分子化合物的初步筛选

肝癌发病率高，中位生存期短，发病机制未完全阐明。肝癌转移是肝癌复发、致死的重要原因，目前常规治疗尚不能有效控制肝癌转移，因此进一步探讨其发病机制，开发新靶点药物是肝癌治疗研究的焦点和发展趋势。CD147分子是一个癌特异性的、新型广谱的生物标志物，本实验室研发的CD147分子的特异性抗体HAb18能竞争性结合CD147分子的功能性位点，抑制MMPs分泌和肝癌侵袭转移。本项目拟解析CD147-HAb18抗原抗体复合物的晶体结构，明确CD147分子诱导MMPs分泌的功能性位点，为相关药物的研发提供一个新的原子水平的精细结构平台。同时将基于该平台，采用计算机辅助的药物筛选技术，筛选与CD147分子功能性位点有良好结合活性的小分子化合物，并通过明胶酶谱实验、体外肿瘤侵袭模型和肝癌裸鼠转移模型筛选具有抗肝癌转移活性的小分子化合物，为将靶向CD147分子的小分子化合物开发为新的肝癌靶向治疗药物提供依据。

Hepatocellular carcinoma is of high morbidity and short median survival time. The molecular mechanism of liver oncogenesis has not been well elucidated. While metastasis is the significant cause of HCC recurrence and mortality, it can not be effectively controlled by regular treatment. Therefore, study on mechanism of HCC and molecular targeting drugs has become the trend and the focus of research. CD147 is a broad spectrum carcinoma-specific biomarker. HAb18, a monoclonal antibody against CD147 developed in our lab, binds to the active site of CD147 and inhibits MMPs secretion, HCC invasion and metastasis. In this study, we will determine the crystal structure of the extracellular region of CD147 in complex with HAb18 Fab and reveal the active site of CD147 for MMPs induction. Furthermore, we will screen the small molecules with the activity to block the active site of CD147 using CADD based on the complex structure. Also, we will test the anti-metastasis activity of the small molecules using gelatin zymography analysis, in vitro tumor cell invasion assay and metastatic HCC models in nude mice, which will provide scientific basis for the development of small molecular weight drugs targeting CD147 for HCC treatment.