Chemical genomics approach leads to the identification of hesperadin, an aurora B kinase inhibitor, as a broad-spectrum influenza antiviral

Yanmei Hu, Jiantao Zhang, Rami Musharrafieh, Raymond Hau, Chunlong Ma, Jun Wang

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Influenza viruses are respiratory pathogens that are responsible for annual influenza epidemics and sporadic influenza pandemics. Oseltamivir (Tamiflu®) is currently the only FDA-approved oral drug that is available for the prevention and treatment of influenza virus infection. However, its narrow therapeutic window, coupled with the increasing incidence of drug resistance, calls for the next generation of influenza antivirals. In this study, we discovered hesperadin, an aurora B kinase inhibitor, as a broad-spectrum influenza antiviral through forward chemical genomics screening. Hesperadin inhibits multiple human clinical isolates of influenza A and B viruses with single to submicromolar efficacy, including oseltamivir-resistant strains. Mechanistic studies revealed that hesperadin inhibits the early stage of viral replication by delaying the nuclear entry of viral ribonucleoprotein complex, thereby inhibiting viral RNA transcription and translation as well as viral protein synthesis. Moreover, a combination of hesperadin with oseltamivir shows synergistic antiviral activity, therefore hesperadin can be used either alone to treat infections by oseltamivir-resistant influenza viruses or used in combination with oseltamivir to delay resistance evolution among oseltamivir-sensitive strains. In summary, the discovery of hesperadin as a broad-spectrum influenza antiviral offers an alternative to combat future influenza epidemics and pandemics.

Original languageEnglish (US)
Article number1929
JournalInternational Journal of Molecular Sciences
Volume18
Issue number9
DOIs
Publication statusPublished - Sep 8 2017

    Fingerprint

Keywords

  • Aurora kinase
  • Broad-spectrum antiviral
  • Combination therapy
  • Drug resistance
  • Hesperadin
  • Host-targeting antiviral
  • Influenza

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Computer Science Applications
  • Spectroscopy
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this