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|Title: ||E339…R416 salt bridge of nucleoprotein as a feasible target for influenza virus inhibitors|
|Authors: ||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|
|Issue Date: ||2018-03-26T06:40:53Z
|Publisher: ||Proceedings of the National Academy of Sciences of the United States of America|
|Abstract: ||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).
|Appears in Collections:||[生命科學系] 期刊論文|
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