结核分枝杆菌蛋白酪氨酸磷酸酶B的双齿抑制剂的设计合成及活性研究

Tuberculosis (TB) is a major infectious disease caused by Mycobacterium tuberculosis (Mtb), and is a major worldwide threat to public health. Mycobacterium protein tyrosine phosphatase B (mPTPB) are virulent phosphatases secreted into the host cell by Mtb, which play important roles in interference of host signaling. Mycobacterium tuberculosis protein tyrosine phosphatases B (MptpB) mediate pathogen survival in macrophages by the dephosphorylation of host proteins that are involved in key pathways of the immune system. Consequently, bidentate inhibitors of mPTPB are expected to serve as anti-TB agents with a novel mode of action. In this work, our aim is to design and synthesize bidentate inhibitors, which is binding both active site and unique nearby subpockets, and to study the interaction between mPTPB and bidentate inhibitors by X-ray crystallographic analysis and molecular modeling study. This work will become available for setting up the interaction model between mPTPB and bidentate inhibitors, guiding further optimization of bidentate inhibitors and developing anti- tuberculosis drug lead compound.

结核病（TB）是由结核分枝杆菌造成的传染性疾病，它严重地威胁着全球人类的健康。作为结核病的病原菌，结核分枝杆菌在感染宿主细胞时，会分泌蛋白磷酸酶mPTPB 到细胞中。mPTPB 会干扰宿主细胞的信号转导，从而使结核杆菌逃避宿主免疫系统灭杀并存活。设计合成高效特异性的mPTPB双齿抑制剂必将极大促进新型抗结核药物先导化合物的发展，为结核病的治疗提供新途径。本项目中，将以获取靶向mPTPB酶催化亚基和非保守性亚基（第二结合位点）的双齿抑制剂为目标，设计合成双齿抑制剂，基于双齿抑制剂与mPTPB复合物的结构生物学信息，结合分子模拟研究，寻找和确定第二结合位点的氨基酸序列。这项工作将有助于构建双齿抑制剂与mPTPB之间的作用模型，为进一步修饰双齿抑制剂结构、发展抗结核药物的先导化合物奠定了基础。