寨卡病毒可突破血胎屏障导致胎儿感染而引起新生儿小头畸形。2016年WHO宣布将寨卡病毒感染及小头症列为全球紧急公共卫生事件。非结构蛋白NS1对寨卡病毒的感染、复制和入侵至关重要；NS5分为N端和C端两个结构域，分别具有甲基转移酶和RNA依赖的RNA聚合酶活性，都是很好的药物筛选靶点。前期针对NS5进行筛选，从海洋微生物中筛选到了2个C端和3个N端小分子抑制剂。分子对接发现3个化合物与NS5甲基转移酶有很好的结合力，细胞实验显示化合物对寨卡病毒感染有一定抑制效果。拟通过优化培养基和培养条件，利用HPLC-MS追踪的方法，获得更多活性化合物的类似物；并通过进一步的筛选发现新的海洋微生物来源的针对NS1或者NS5蛋白的活性化合物；利用细胞模型验证这些化合物的抗病毒效果；通过分子对接、蛋白和小分子共结晶的单晶结构分析，以及结构生物学手段探讨活性化合物与靶点的作用位点和方式，为开发新的药物奠定基础。

The quick spread of Zika virus (ZIKV) through the world has fetched this previously overlooked virus into the worldwide concern. The ZIKV belongs to the Flaviviridae family and the Flavivirus genus, and is primarily transmitted by species of aedes mosquitoes. The clinical symptoms of ZIKV infections are usually mild, but ZIKV infection during pregnancy can cause a birth defect of the brain called microcephaly and other severe fetal brain defects. Other problems have been also detected among fetuses and infants infected with Zika virus before birth, such as defects of the eye, hearing deficits, and impaired growth. In addition, ZIKV is also linked to a sudden increase in the reported cases of Guillain Barré syndrome. However, available treatments for ZIKV infection are limited, as there is currently no effective chemoprophylaxis or vaccination against infection. The reported crystal structures of Zika virus NS1 and NS5 reveals conserved drug targets. By screening the marine microbial natural compound library, 2 and 3 hits showed inhibitory effect against NS5 polymerase and methyltransferase, respectively. Three compounds showed significant binding affinity with NS5 methyltransferase and one compound displayed inhibitory effect on Zika virus in vitro. The current proposal will focus on the following points: to optimize the culture condition to identify more analogues of the active compound by HPLC-MS directed method; to screening more inhibitors against NS1 and NS5 from marine microbial natural product library; to verify the anti-virus effect of these compounds. The mode of action and active sites of these lead compounds will be investigated by docking, co-crystallization of inhibitors and proteins for drug discovery against ZIKV.