Discovery of Influenza Polymerase PA-PB1 Interaction Inhibitors Using an in Vitro Split-Luciferase Complementation-Based Assay

Jiantao Zhang, Yanmei Hu, Nan Wu, Jun Wang

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)74-82
Number of pages9
JournalACS Chemical Biology
Volume15
Issue number1
DOIs
StatePublished - Jan 17 2020

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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