TY - JOUR
T1 - Chemical genomics approach leads to the identification of hesperadin, an aurora B kinase inhibitor, as a broad-spectrum influenza antiviral
AU - Hu, Yanmei
AU - Zhang, Jiantao
AU - Musharrafieh, Rami
AU - Hau, Raymond
AU - Ma, Chunlong
AU - Wang, Jun
N1 - Funding Information:
Acknowledgments: This work was supported by University of Arizona startup funds and NIH AI 119187 to Jun Wang, Rami Musharrafieh was supported by the NIH training grant T32 GM008804. We thank David Bishop for proofreading and editing the manuscript.
Publisher Copyright:
© 2017 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2017/9/8
Y1 - 2017/9/8
N2 - 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.
AB - 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.
KW - Aurora kinase
KW - Broad-spectrum antiviral
KW - Combination therapy
KW - Drug resistance
KW - Hesperadin
KW - Host-targeting antiviral
KW - Influenza
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U2 - 10.3390/ijms18091929
DO - 10.3390/ijms18091929
M3 - Article
C2 - 28885544
AN - SCOPUS:85029184353
SN - 1661-6596
VL - 18
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 9
M1 - 1929
ER -