E339…R416 salt bridge of nucleoprotein as a feasible target for influenza virus inhibitors
| Autor: | Hui Wen Liu, Ming-Daw Tsai, Yih-Shyun E. Cheng, Pang-Hung Hsu, Chi-Huey Wong, Yu-Hou Chen, Ying-Ta Wu, Chao-Jung Wu, An-Suei Yang, Pei-Yu Wu, Fu-Yang Lin, Hua-Ting Hsu, Gialih Lin, Yu-Fang Shen, Mengi Lin, Shao-Ying Chu |
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| Rok vydání: | 2011 |
| Předmět: |
Models
Molecular Protein Conformation Blotting Western Static Electricity Orthomyxoviridae Mutation Missense Virus Replication Virus Cell Line Dogs Drug Delivery Systems Animals Binding site Fluorescent Antibody Technique Indirect Luciferases DNA Primers Ribonucleoprotein Virtual screening Multidisciplinary biology Circular Dichroism Hydrogen Bonding biology.organism_classification Virology Nucleoprotein Nucleoproteins Viral replication Multiprotein Complexes Physical Sciences Salt bridge Protein Multimerization Ultracentrifugation |
| Zdroj: | Proceedings of the National Academy of Sciences. 108:16515-16520 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1113107108 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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