抗登革热病毒NS5 RdRp抑制剂的设计、合成及活性研究

登革病毒( dengue virus, DENV) 是严重危害人类身体健康和生命的主要病毒，登革热也是WHO列入10大严重威胁人类身体健康的疾病, 全球每年有4亿人感染登革热病毒。然而，目前缺乏广泛预防DENV的疫苗或特异性药物，抗登革病毒药物的研发迫在眉睫。NS5 RdRp聚合酶因其在病毒基因组复制过程中的核心作用而成为抗病毒药物研究的重要靶点。前期工作中，我们发现了DENV NS5 RdRp抑制剂WYM-19，其对4种血清型DENV的均有抑制作用，且对宿主Vero细胞毒性很小，具有深入开发研究的价值。本项目拟采用计算机辅助药物设计的多元策略，设计并合成靶向DENV NS5-RdRp的小分子抑制剂，最后通过生物活性评价和药物作用机制研究，提供在体外、体内有效抑制登革病毒的先导化合物，为开发优良的抗登革热药物候选物奠定基础.

Dengue virus (DENV) is one of the major viruses that seriously endanger human health and life. Dengue fever is also listed as one of the top 10 diseases seriously threatening human health by WHO. Dengue virus (DENV) annually infects 400 million people worldwide. Unfortunately, there is lack of widely protective vaccine or drugs against DENV. Therefore, it is very urgent to develop drugs that can resist dengue virus.. DENV NS5 RdRp performs both minus-strand and plus-strand RNA synthesis during replication. Because NS5 RdRp has no mammalian counterpart and its protein sequence is highly conserved among different DENV subtypes, it offers an attractive opportunity for discovery of new antiviral agents. Previously, Our HTS campaigns led to the identification of compound WYM-19 as DENV NS5 RdRp inhibitor, which displayed antiviral activity in the cell-based assays for all four dengue serotypes at micromolar concentrations，and has little toxicity to the host Vero cells, so it is of great value for further development and research. In this study, basing on the WYM- 17 and DENV NS5 RdRp complex model，combining with computer aided drug design diversified strategy, we will design and synthesis of a series of new DENV NS5 RdRp inhibitors and analysis their anti-DENV activity in vivo and vitro, interaction mechanism as well as the structure-activity relationship. With these efforts, we hope to lay a foundation for the development of effective drugs for the prevention and control of dengue fever.