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Int. J. Mol. Sci. 2017, 18(9), 1929; doi:10.3390/ijms18091929

Chemical Genomics Approach Leads to the Identification of Hesperadin, an Aurora B Kinase Inhibitor, as a Broad-Spectrum Influenza Antiviral

1
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA
2
Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA
3
BIO5 Institute, University of Arizona, Tucson, AZ 85721, USA
*
Author to whom correspondence should be addressed.
Received: 22 July 2017 / Revised: 24 August 2017 / Accepted: 6 September 2017 / Published: 8 September 2017
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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. View Full-Text
Keywords: influenza; broad-spectrum antiviral; host-targeting antiviral; hesperadin; drug resistance; combination therapy; aurora kinase influenza; broad-spectrum antiviral; host-targeting antiviral; hesperadin; drug resistance; combination therapy; aurora kinase
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Hu, Y.; Zhang, J.; Musharrafieh, R.; Hau, R.; Ma, C.; Wang, J. Chemical Genomics Approach Leads to the Identification of Hesperadin, an Aurora B Kinase Inhibitor, as a Broad-Spectrum Influenza Antiviral. Int. J. Mol. Sci. 2017, 18, 1929.

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