National Taiwan Ocean University Institutional Repository:Item 987654321/45554
English  |  正體中文  |  简体中文  |  全文笔数/总笔数 : 28595/40626
造访人次 : 4206353      在线人数 : 51
RC Version 4.0 © Powered By DSPACE, MIT. Enhanced by NTU Library IR team.
搜寻范围 进阶搜寻

jsp.display-item.identifier=請使用永久網址來引用或連結此文件: http://ntour.ntou.edu.tw:8080/ir/handle/987654321/45554

题名: E339…R416 salt bridge of nucleoprotein as a feasible target for influenza virus inhibitors
作者: Yu-Fang Shen;Yu-Hou Chen;Shao-Ying Chu;Meng-I Lin;Hua-Ting Hsu;Pei-Yu Wu;Chao-Jung Wu;Hui-Wen Liu;Fu-Yang Lin;Gialih Lin;Pang-Hung Hsu;An-Suei Yang;Yih-Shyun E. Cheng;Ying-Ta Wu;Chi-Huey Wong;Ming-Daw Tsai
贡献者: 國立臺灣海洋大學:生命科學系
日期: 2011
上传时间: 2018-03-26T06:40:53Z
出版者: Proceedings of the National Academy of Sciences of the United States of America
摘要: Abstract: The nucleoprotein (NP) of the influenza virus exists as trimers, and its tail-loop binding pocket has been suggested as a potential target for antiinfluenza therapeutics. The possibility of NP as a drug target was validated by the recent reports that nucleozin and its analogs can inhibit viral replication by inducing aggregation of NP trimers. However, these inhibitors were identified by random screening, and the binding site and inhibition mechanism are unclear. We report a rational approach to target influenza virus with a new mechanism—disruption of NP–NP interaction. Consistent with recent work, E339A, R416A, and deletion mutant Δ402–428 were unable to support viral replication in the absence of WT NP. However, only E339A and R416A could form hetero complex with WT NP, but the complex was unable to bind the RNA polymerase, leading to inhibition of viral replication. These results demonstrate the importance of the E339…R416 salt bridge in viral survival and establish the salt bridge as a sensitive antiinfluenza target. To provide further support, we showed that peptides encompassing R416 can disrupt NP–NP interaction and inhibit viral replication. Finally we performed virtual screening to target E339…R416, and some small molecules identified were shown to disrupt the formation of NP trimers and inhibit replication of WT and nucleozin-resistant strains. This work provides a new approach to design antiinfluenza drugs.

The RNA-dependent RNA polymerase (RDRP) of the influenza A virus is composed of polymerase basic protein 1 (PB1), basic protein 2 (PB2), and acidic protein (PA) (1). The function of RDRP for viral replication requires association with the nucleoprotein (NP) (2) to form the ribonucleoprotein (RNP) complex. Only low resolution structures of the RNP complex are available from cryo-EM studies (2–9), whereas high resolution structures have been reported for some individual components or fragments (10–12). Crystal structures of NP indicate that it exists in trimers (13, 14), with the tail-loop (residues 402–428) region playing an important role in the trimerization (Fig. 1A). Based on the structural information, it was suggested that the tail-loop binding pocket could be a target for antiinfluenza therapeutics (13, 14).
URI: http://ntour.ntou.edu.tw:8080/ir/handle/987654321/45554
显示于类别:[生命科學系] 期刊論文

文件中的档案:

档案 描述 大小格式浏览次数
index.html0KbHTML51检视/开启


在NTOUR中所有的数据项都受到原著作权保护.

 


著作權政策宣告: 本網站之內容為國立臺灣海洋大學所收錄之機構典藏,無償提供學術研究與公眾教育等公益性使用,請合理使用本網站之內容,以尊重著作權人之權益。
網站維護: 海大圖資處 圖書系統組
DSpace Software Copyright © 2002-2004  MIT &  Hewlett-Packard  /   Enhanced by   NTU Library IR team Copyright ©   - 回馈