寨卡病毒感染可导致成人格林-巴利综合征以及胎儿小头症等严重神经系统先天发育障碍。临床上尚无针对寨卡病毒感染的疫苗和抗病毒药物。近期，寨卡病毒甲基转移酶（MTase）等关键蛋白晶体结构的解析为抗寨卡药物的设计奠定了基础。寨卡病毒MTase的晶体结构显示，其活性位点具有一个“眼镜”型口袋，是抗病毒药物设计的潜在靶点。前期，我们基于同源模建的寨卡病毒MTase结构，针对上述靶点首次设计并合成了一系列苯并噻吩类全新结构化合物；进一步基于寨卡病毒国内分离株建立了抗寨卡药物评价体系，并利用该体系证实，该系列化合物具有良好抗寨卡活性。本研究从最新解析的寨卡病毒MTase晶体结构入手，综合利用分子相互作用、体外活性评价、结构生物学等多种手段，对该系列化合物进行多轮优化设计，优选化合物利用基于国内株的小鼠及非人灵长类感染模型对优选化合物进行体内评价，最终希望获得在体内具有良好治疗活性的抗寨卡病毒候选化合物。

Zika virus (ZIKV) is associated with Guillain–Barre´ syndrome (GBS) in adults and severe congenital neurological abnormalities in fetus such as microcephaly. No vaccines or antiviral drugs are clinically available for ZIKV infections. Crystal structures of ZIKV key proteins including NS5 methyltransferase (MTase) domain are resolved recently, which paved way for structure-based drug discovery against ZIKV. Structure of MTase revealed an ‘eyeglass’ shaped pocket in its catalytic site, which is a potential pocket for anti-ZIKV inhibitor design. Previously, we predicted the ZIKV MTase 3D structure by homology modeling, and designed and synthesized a series of compounds with the core of benzothiophene. Using an live-virus based in vitro screening model, we obtained among these compounds several hits with ideal antiviral efficiency. In this research, based on the recently resolved 3D structure of ZIKV MTase, we will applicate multiple technics including molecular interaction assay, in vitro evaluation assay and co-crystallization assay to optimize the inhibitors. Finally, we will evaluate the in vivo therapeutic efficacy using established mouse and non-human primate ZIKV infection models.