基于肠道病毒71型3D聚合酶的活性天然产物研究

Rencent outbreaks of hand, foot and mouth disease were out of control, which is a serious threat to infant health in our country. There was no effective vaccine or antiviral drugs currently in the clinic. We found that lycorine not only inhibited EV71 replication in vitro, but aslo lycorine treatment of mice challenged with a lethal dose of EV71 resulted in reduction of mortality, which were associated with 3D polymerase. Based on molecular docking of 3D polymerase, we designed and synthsized a series of lycorine derivatives.The lead was identified with good lipid solubility, high activity and low toxicity. We performed the further study to lycorine in this project. Lycorine was modified in the 1-OH with 2-OH or 2-ketone. The derivatives was detected against EV71 and 3D polymerase in vitro, and the structure-activity relationships were discussed. The active derivatives was also determided in vivo.This Research will lay foundation for the development of drugs against hand, foot and mouth disease.

近年来爆发的手足口病疫情仍然没有得到遏制，严重威胁我国婴幼儿的健康。目前临床上缺少疫苗和有效药物。我们在前期研究中发现石蒜碱不仅在体外能抑制EV71的复制，而且在体内能降低手足口模型小鼠的死亡率，且此活性与3D聚合酶相关。基于3D聚合酶的分子对接，我们设计并合成了一系列石蒜碱衍生物，筛选出脂溶性好、活性提高、毒性降低的先导化合物。本项研究拟对石蒜碱进行深入研究：保留2位的羟基或者氧化成酮，对其1位进行结构修饰；对衍生物进行体外抗病毒与3D聚合酶活性测定，探讨构效关系；对于活性衍生物，进行体内活性的验证，为研发手足口病的治疗药物鉴定基础。

近年来爆发的手足口病疫情威胁婴幼儿的健康，目前临床上缺少有效的药物。我们在前期研究中发现石蒜碱不仅在体外能抑制EV71的复制，而且在体内能降低手足口模型小鼠的死亡率，且此活性与3D聚合酶相关。本项目基于前期结果，共合成衍生物的数量为82个；对衍生物进行了体外抗EV71的测试，探讨了构效关系，寻找到了具有高效、低毒、溶解性好的活性衍生物；考察了衍生物对流感病毒A型（H3N2）、柯萨奇病毒B3型（CVB3）、单纯疱疹病毒1型（HSV-1）的抑制活性；对衍生物LY-32与LY-55进行了体内活性的验证；对衍生物LY-32与LY-55进行了药代与毒性实验；对衍生物LY-55进行了制剂研究；初步探索了衍生物LY-55的作用机制；申请中国专利一项与PCT专利各一项；衍生物技术转让合同一份；申请到基金一项；发表会议论文一篇，SCI论文正在整理，预计2019年发表；协助培养硕士研究生一名。本项目为研发手足口病的治疗药物鉴定了基础。