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

HCV 感染的病毒和宿主靶向抑制因子的高通量筛选

• 批准号: 21390226
• 负责人: SAKAMOTO Naoya
• 金额: $ 11.4万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21390226/
• 关键词: C型肝炎; レプリコンシステム; HCV-Feoレプリコン; HCV-JFH1培養系; 小分子ライブラリー

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.

在本研究期间，我们利用HCV感染和复制细胞培养，对抑制HCV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)通过使用HCV Feo复制子，我们进行了基于细胞的8，000个多样性导向合成（DOS）化合物的筛选。我们最初选择了41种抑制HCV复制的化合物，并进一步验证了5种具有低IC 50的环氧化合物。(2)我们筛选了4000种合成化合物，并鉴定了5种抑制HCV复制子和HCV-JFH 1细胞培养的化合物。我们进一步进行了构效关系（SAR）分析，并确定了抗病毒活性的基本分子结构。(3)我们筛选了富含丝氨酸（SR）的蛋白激酶，并确定了4个抗HCV化合物。综合以上结果，我们将进一步加深对HCV感染生命周期和抗病毒活性分子靶点的认识。

项目成果

The inhibitory effect on hepatitis C virus infection of a triterpenoid compound, with or without interferon-alpha

一种三萜类化合物在有或没有干扰素-α的情况下对丙型肝炎病毒感染的抑制作用

• 发表时间: 2011
• 期刊: Antimicrob Agents Chemother
• 作者: Watanabe T;Sakamoto N;Nakagawa M;Kakinuma S;Itsui Y;Nishimura-Sakurai Y;Ueyama M;Funaoka Y;Kitazume A;Nitta S;Kiyohashi K;Murakawa M;Azuma S;Tsuchiya K;Oooka S;Watanabe M
• 通讯作者: Watanabe M

A new method for induced fit docking (GENIUS) and its application to virtual screening of novel HCV NS3-4A protease inhibitors

诱导拟合对接新方法（GENIUS）及其在新型HCV NS3-4A蛋白酶抑制剂虚拟筛选中的应用

• DOI: 10.1016/j.bmc.2011.09.023
• 发表时间: 2011
• 期刊: Bioorganic & Medicinal Chemistry
• 影响因子: 3.5
• 作者: Takaya D;Sakamoto N;et al.
• 通讯作者: et al.

Studies on virus kinetics using injbctious fluorescence-tagged hepatitis C ViruS Cell Culture.

使用注射荧光标记的丙型肝炎病毒细胞培养物研究病毒动力学。

• 发表时间: 2011
• 期刊: Hepatology Research
• 影响因子: 4.2
• 作者: Machi Yamamoto;Naoya Sakamoto;et al.
• 通讯作者: et al.

A high-content screening assay using infectious fluorescence-tagged hepatitis C virus reveals candidates fo rsmall molecule inhibitors of viral entry

使用传染性荧光标记丙型肝炎病毒的高内涵筛选测定揭示了病毒进入小分子抑制剂的候选物

• 发表时间: 2011
• 作者: Kusano-Kitazume A;Sakamoto N;Okuno Y;Yamamoto M;Sekine-Osajima Y;Nakagawa M;Kakinuma S;Kiyohashi K;Nitta S;Murakawa M;Hagiwara M;Watanabe M
• 通讯作者: Watanabe M

Antiviral effect of a novel interferon-inducible protein, IFI-27, against hepatitis C virus replication

新型干扰素诱导蛋白 IFI-27 对丙型肝炎病毒复制的抗病毒作用

• 发表时间: 2011
• 作者: Itsuil Y;Sakamoto N;Watanabe M;et al.
• 通讯作者: et al.