Discovery of Influenza Polymerase PA–PB1 Interaction Inhibitors Using an In Vitro Split-Luciferase Complementation-Based Assay
Autor: | Yanmei Hu, Jiantao Zhang, Jun Wang, Nan Wu |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Oseltamivir medicine.drug_class viruses Biology 01 natural sciences Biochemistry 03 medical and health sciences chemistry.chemical_compound High-Throughput Screening Assays medicine Luciferase Polymerase 010405 organic chemistry Amantadine virus diseases General Medicine Virology 0104 chemical sciences Complementation 030104 developmental biology Viral replication chemistry biology.protein Molecular Medicine Antiviral drug medicine.drug |
Zdroj: | ACS Chemical Biology. 15:74-82 |
ISSN: | 1554-8937 1554-8929 |
Popis: | The limited therapeutic options and increasing drug-resistance call for next-generation influenza antivirals. Due to the essential function in viral replication and high sequence conservation among influenza viruses, influenza polymerase PA-PB1 protein-protein interaction becomes an attractive drug target. Here, we developed an in vitro split luciferase complementation-based assay to speed up screening of PA-PB1 interaction inhibitors. By screening 10,000 compounds, we identified two PA-PB1 interaction inhibitors, R160792 and R151785, with potent and broad-spectrum antiviral activity against a panel of influenza A and B viruses, including amantadine-, oseltamivir-, or dual resistant strains. Further mechanistic study reveals that R151785 inhibits PA nuclear localization, reduces the levels of viral RNAs and proteins, and inhibits viral replication at the intermediate stage, all of which are in line with its antiviral mechanism of action. Overall, we developed a robust high throughput-screening assay for screening broad-spectrum influenza antivirals targeting PA-PB1 interaction and identified R151785 as a promising antiviral drug candidate. |
Databáze: | OpenAIRE |
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