請用此 Handle URI 來引用此文件: http://hdl.handle.net/11455/71170
標題: E339 ... R416 salt bridge of nucleoprotein as a feasible target for influenza virus inhibitors
作者: Shen, Y.F.
Chen, Y.H.
Chu, S.Y.
Lin, M.I.
Hsu, H.T.
Wu, P.Y.
Wu, C.J.
Liu, H.W.
Lin, F.Y.
Lin, G.
Hsu, P.H.
Yang, A.S.
Cheng, Y.S.E.
Wu, Y.T.
Wong, C.H.
Tsai, M.D.
關鍵字: mutational analysis
h5n1 nucleoprotein
crystal-structure
amino-acids
ribonucleoprotein
rna
identification
oligomerization
subunit
reveals
期刊/報告no:: Proceedings of the National Academy of Sciences of the United States of America, Volume 108, Issue 40, Page(s) 16515-16520.
摘要: 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 Delta 402-428 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.
URI: http://hdl.handle.net/11455/71170
ISSN: 0027-8424
文章連結: http://dx.doi.org/10.1073/pnas.1113107108
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