Evaluation of kinase inhibitors as potential therapeutics for flavivirus infections
The recent introduction of Zika virus (ZIKV), the recurrence of dengue virus (DENV), and the lethality of yellow fever virus (YFV) have had a significant impact on Brazilian society and public health. Here, we targeted two cellular kinases implicated in cell proliferation and cancer that are also im...
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| Veröffentlicht in: | Archives of virology 2021-05, Vol.166 (5), p.1433-1438 |
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| creator | Valencia, Hugo J. de Aguiar, Mara C. A. M. Costa, Mariana A. Mendonça, Diogo C. Reis, Erik V. Arias, Nídia E. C. Drumond, Betânia P. Bonjardim, Cláudio A. |
| description | The recent introduction of Zika virus (ZIKV), the recurrence of dengue virus (DENV), and the lethality of yellow fever virus (YFV) have had a significant impact on Brazilian society and public health. Here, we targeted two cellular kinases implicated in cell proliferation and cancer that are also important for viral replication: mitogen-activated protein kinase kinase (MEK) and Src. We used two MEK inhibitors – trametinib and selumetinib – and two Src inhibitors – saracatinib and bosutinib – to inhibit ZIKV, DENV, and YFV replication in cell culture. The cytotoxicity of the four inhibitors was determined by the observation of abnormal morphology and quantification of adherent cells by crystal violet staining. The antiviral activity of these drugs was assessed based on the reduction of plaque-forming units in cell culture as evidence of the inhibition of the replication of the selected flaviviruses. All four inhibitors showed antiviral activity, but among them, trametinib was the safest and most efficacious against all of the viruses, inhibiting the replication of ZIKV and YFV by 1000-fold, and DENV2/3 by nearly 100-fold. This pan-antiviral effect shows that trametinib could be repurposed for the treatment of flaviviral infections. |
| doi_str_mv | 10.1007/s00705-021-05021-1 |
| format | Article |
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A. M. ; Costa, Mariana A. ; Mendonça, Diogo C. ; Reis, Erik V. ; Arias, Nídia E. C. ; Drumond, Betânia P. ; Bonjardim, Cláudio A.</creator><creatorcontrib>Valencia, Hugo J. ; de Aguiar, Mara C. A. M. ; Costa, Mariana A. ; Mendonça, Diogo C. ; Reis, Erik V. ; Arias, Nídia E. C. ; Drumond, Betânia P. ; Bonjardim, Cláudio A.</creatorcontrib><description>The recent introduction of Zika virus (ZIKV), the recurrence of dengue virus (DENV), and the lethality of yellow fever virus (YFV) have had a significant impact on Brazilian society and public health. Here, we targeted two cellular kinases implicated in cell proliferation and cancer that are also important for viral replication: mitogen-activated protein kinase kinase (MEK) and Src. We used two MEK inhibitors – trametinib and selumetinib – and two Src inhibitors – saracatinib and bosutinib – to inhibit ZIKV, DENV, and YFV replication in cell culture. The cytotoxicity of the four inhibitors was determined by the observation of abnormal morphology and quantification of adherent cells by crystal violet staining. The antiviral activity of these drugs was assessed based on the reduction of plaque-forming units in cell culture as evidence of the inhibition of the replication of the selected flaviviruses. All four inhibitors showed antiviral activity, but among them, trametinib was the safest and most efficacious against all of the viruses, inhibiting the replication of ZIKV and YFV by 1000-fold, and DENV2/3 by nearly 100-fold. 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We used two MEK inhibitors – trametinib and selumetinib – and two Src inhibitors – saracatinib and bosutinib – to inhibit ZIKV, DENV, and YFV replication in cell culture. The cytotoxicity of the four inhibitors was determined by the observation of abnormal morphology and quantification of adherent cells by crystal violet staining. The antiviral activity of these drugs was assessed based on the reduction of plaque-forming units in cell culture as evidence of the inhibition of the replication of the selected flaviviruses. All four inhibitors showed antiviral activity, but among them, trametinib was the safest and most efficacious against all of the viruses, inhibiting the replication of ZIKV and YFV by 1000-fold, and DENV2/3 by nearly 100-fold. 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| subjects | Adherent cells Animals Antiviral activity Antiviral agents Antiviral Agents - pharmacology Biomedical and Life Sciences Biomedicine Brief Report Cell culture Cell Line Cell proliferation Cell Survival - drug effects Chlorocebus aethiops Cricetinae Cytology Cytotoxicity Dengue fever Flavivirus - classification Flavivirus - drug effects Flavivirus - physiology Infectious Diseases Kinases Lethality MAP kinase Medical Microbiology MEK inhibitors Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors Protein kinase Protein Kinase Inhibitors - pharmacology Public health Replication Src protein src-Family Kinases - antagonists & inhibitors Vero Cells Virology Virus Replication - drug effects Viruses |
| title | Evaluation of kinase inhibitors as potential therapeutics for flavivirus infections |
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