光激活多肽配体的分子探针可视化酪氨酸激酶动力学的基础研究

By far, the tyrosine kinase is utmost important target for the research of anticancer drugs because it is most closely related to tumor growth, metastasis and angiogenesis. We will leverage peptide probes based on fluorescence resonace energy transfer to visualize the conformational changes of tyrosine kinase by means of photoactivation. Based on the above observation, we thus expect to elucidate the change of the activities of tyrosine kinase. Meanwhile, we want also to employ the probe to track the process of transduction cell signaling when it is bound to kinase. Our results could provide theoretical guidance for the development of anticancer drugs.

目前的研究表明，酪氨酸激酶与肿瘤的生长，转移和血管生成密切相关，并作为抗肿瘤药物靶点得到了广泛的关注。本项目通过设计合成基于光激活荧光共振能量多肽配体的荧光分子探针来可视化酪氨酸激酶构象变化的动力学，并阐明酪氨酸激酶在磷酸化前后的活性变化。同时，通过光激活的分子探针来观察酪氨酸激酶由单体到二聚体变化前后的信号传导过程。我们研究结果将为抗肿瘤药物的开发提供理论方面的指导。

到目前为止，酪氨酸激酶作为抗肿瘤药物靶点仍受到了广泛的关注。本项目通过设计合成具有荧光共振能量转移的多肽分子探针实现了对原位肿瘤细胞的选择性识别。在此基础上，对天然抗肿瘤多肽序列进行单个氨基酸突变来调控多肽药物的自组装行为。研究结果发现，这种方法不仅可以增强多肽药物对肿瘤细胞的渗透，而且增强了对肿瘤治疗效果。我们也开发了非天然氨基酸装订的环肽分子，该环肽能有效抑制癌细胞的生长。该策略为抗肿瘤药物的研发提供了新的研究思路和理论方面的指导，相关研究成果有望进入临床应用