基于MD-2靶标的紫杉烷分子裁剪及其作用机理的研究

MD-2作为天然免疫识别过程的重要调控分子，有可能成为炎症性疾病治疗的"新靶点"。本项目提出以MD-2为靶标对紫杉烷进行设计和分子裁剪，发展新型高效低毒紫杉烷类化合物；高通量筛选活性化合物，对其生物活性进行综合评价，发现高度"选择性"或"多效性"先导化合物，丰富药用样品资源库；在此基础上，深入研究新活性紫杉烷的活性构象；并以具有专一性的新活性荧光分子作为探针开展活细胞内MD-2的实时视见研究，研究其与MD-2相互作用，阐明其生物活性机理。该课题的研究将可能拓展多作用机制或免疫抑制作用药物的研究，有助于阐明紫杉醇多途径、多层次地发挥抗肿瘤的多作用机理，对更有效地开发紫杉烷类化合物治疗其它疾病的潜在价值具有重要意义，为红豆杉植物资源的研究利用开辟新的途径。

As an important regulatory molecule in the process of innate immune recognition, MD-2 will probably become a new target in the treatment of inflammatory diseases.This project proposes the molecular design and tailoring of taxanes targeting to MD-2, developing novel derivatives with high efficiency and low toxicity, high-throughput screening of active compounds, comprehensively evaluating their biological activity, discovering lead compounds with high "selectivity" or "pleiotropy", enriching medicinal samples repository.On this basis,we will further carry on the research of the taxane's active conformation and promote the real-time visible research to MD-2 in living cells with new active fluorescent molecule probes, so as to study the interaction and illuminate the mechanism of its biological activity. This project will probably expand the research of the multi-mechanism or the immunosuppressive effects of medicine and help to explain the multi-channel and multi-level mechanism of the paclitaxel. It will very likely make a big difference on developing the potential value of the taxanes on the treatment of other diseases more effectively, and explore new paths to the research on the use of yew plant resources.