Screening for Novel Small-Molecule Inhibitors Targeting the Assembly of Influenza Virus Polymerase Complex by a Bimolecular Luminescence Complementation-Based Reporter System
Identifieur interne : 000D37 ( Ncbi/Checkpoint ); précédent : 000D36; suivant : 000D38Screening for Novel Small-Molecule Inhibitors Targeting the Assembly of Influenza Virus Polymerase Complex by a Bimolecular Luminescence Complementation-Based Reporter System
Auteurs : Chunfeng Li [République populaire de Chine] ; Zining Wang [République populaire de Chine] ; Yang Cao [République populaire de Chine] ; Lulan Wang [République populaire de Chine, États-Unis] ; Jingyun Ji [République populaire de Chine] ; Zhigao Chen [République populaire de Chine] ; Tao Deng [République populaire de Chine] ; Taijiao Jiang [République populaire de Chine] ; Genhong Cheng [République populaire de Chine, États-Unis] ; F. Xiao-Feng Qin [République populaire de Chine]Source :
- Journal of Virology [ 0022-538X ] ; 2017.
Abstract
Influenza virus RNA-dependent RNA polymerase consists of three viral protein subunits: PA, PB1, and PB2. Protein-protein interactions (PPIs) of these subunits play pivotal roles in assembling the functional polymerase complex, which is essential for the replication and transcription of influenza virus RNA. Here we developed a highly specific and robust bimolecular luminescence complementation (BiLC) reporter system to facilitate the investigation of influenza virus polymerase complex formation. Furthermore, by combining computational modeling and the BiLC reporter assay, we identified several novel small-molecule compounds that selectively inhibited PB1-PB2 interaction. Function of one such lead compound was confirmed by its activity in suppressing influenza virus replication. In addition, our studies also revealed that PA plays a critical role in enhancing interactions between PB1 and PB2, which could be important in targeting sites for anti-influenza intervention. Collectively, these findings not only aid the development of novel inhibitors targeting the formation of influenza virus polymerase complex but also present a new tool to investigate the exquisite mechanism of PPIs.
Url:
DOI: 10.1128/JVI.02282-16
PubMed: 28031371
PubMed Central: 5309938
Affiliations:
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<affiliation wicri:level="2"><nlm:aff id="aff4">Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA</nlm:aff>
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<wicri:regionArea>Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, California</wicri:regionArea>
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<author><name sortKey="Qin, F Xiao Feng" sort="Qin, F Xiao Feng" uniqKey="Qin F" first="F. Xiao-Feng" last="Qin">F. Xiao-Feng Qin</name>
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<front><div type="abstract" xml:lang="en"><title>ABSTRACT</title>
<p>Influenza virus RNA-dependent RNA polymerase consists of three viral protein subunits: PA, PB1, and PB2. Protein-protein interactions (PPIs) of these subunits play pivotal roles in assembling the functional polymerase complex, which is essential for the replication and transcription of influenza virus RNA. Here we developed a highly specific and robust bimolecular luminescence complementation (BiLC) reporter system to facilitate the investigation of influenza virus polymerase complex formation. Furthermore, by combining computational modeling and the BiLC reporter assay, we identified several novel small-molecule compounds that selectively inhibited PB1-PB2 interaction. Function of one such lead compound was confirmed by its activity in suppressing influenza virus replication. In addition, our studies also revealed that PA plays a critical role in enhancing interactions between PB1 and PB2, which could be important in targeting sites for anti-influenza intervention. Collectively, these findings not only aid the development of novel inhibitors targeting the formation of influenza virus polymerase complex but also present a new tool to investigate the exquisite mechanism of PPIs.
</p>
<p><bold>IMPORTANCE</bold>
Formation of the functional influenza virus polymerase involves complex protein-protein interactions (PPIs) of PA, PB1, and PB2 subunits. In this work, we developed a novel BiLC assay system which is sensitive and specific to quantify both strong and weak PPIs between influenza virus polymerase subunits. More importantly, by combining <italic>in silico</italic>
modeling and our BiLC assay, we identified a small molecule that can suppress influenza virus replication by disrupting the polymerase assembly. Thus, we developed an innovative method to investigate PPIs of multisubunit complexes effectively and to identify new molecules inhibiting influenza virus polymerase assembly.</p>
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<name sortKey="Wang, Lulan" sort="Wang, Lulan" uniqKey="Wang L" first="Lulan" last="Wang">Lulan Wang</name>
<name sortKey="Wang, Zining" sort="Wang, Zining" uniqKey="Wang Z" first="Zining" last="Wang">Zining Wang</name>
<name sortKey="Wang, Zining" sort="Wang, Zining" uniqKey="Wang Z" first="Zining" last="Wang">Zining Wang</name>
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<country name="États-Unis"><region name="Californie"><name sortKey="Wang, Lulan" sort="Wang, Lulan" uniqKey="Wang L" first="Lulan" last="Wang">Lulan Wang</name>
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