High-throughput screening of virus-and host-targeted suppressors of HCV infection

在本研究期间，我们利用丙型肝炎病毒感染和复制细胞培养，对抑制丙型肝炎病毒复制的药物、生理活性化合物和小分子合成化合物进行了高通量和全面的筛选。(1)利用丙型肝炎病毒Feo复制子，对8000个多样性定向合成(DOS)化合物进行了基于细胞的筛选。我们初步筛选了41个抑制丙型肝炎病毒复制的化合物，并进一步验证了5个环氧化物化合物具有较低的IC50。(2)我们筛选了4000个合成化合物，鉴定出5个化合物抑制丙型肝炎病毒复制子和丙型肝炎病毒JFH1细胞培养。我们进一步进行了构效关系分析，确定了抗病毒活性的基本分子结构。(3)筛选了富含丝氨酸(SR)的蛋白激酶，鉴定了4个抗丙型肝炎病毒的化合物。通过综合以上结果，我们将进一步了解丙型肝炎病毒感染的生命周期和抗病毒活性的分子靶点。

In the present study period, we have conducted high-throughput and comprehensive screening of drugs, physiologically active compounds and small synthetic compounds that suppress HCV replication by using HCV infection and replication cell culture.(1) By using HCV Feo replicon, we conducted cell-based screening of 8, 000 diversity-oriented synthesis(DOS) compounds. We initially selected 41 compounds that suppress HCV replication and further validation identified 5 epoxide compounds that had low IC50.(2) We screened 4, 000 synthetic compounds and identified 5 compounds that suppress HCV replicon and HCV-JFH1 cell culture. We further conducted structure-activity relation(SAR) analyses and identified essential molecular structure for the antiviral activity.(3) We screened serine-rich(SR) protein kinases and identified 4 anti-HCV compounds. By integrating above results, we will further give better understanding of HCV infection life cycle and molecular targets of antiviral activity.