Evaluation of kinase inhibitors as potential therapeutics for flavivirus infections

Valencia, H. J., de Aguiar, M. C. A. M., Costa, M. A., Mendonça, D. C. , Reis, E. V., Arias, N. E. C., Drumond, B. P. and Bonjardim, C. A. (2021) Evaluation of kinase inhibitors as potential therapeutics for flavivirus infections. Archives of Virology, 166(5), pp. 1433-1438. (doi: 10.1007/s00705-021-05021-1) (PMID:33683474) (PMCID:PMC7938686)

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Abstract

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.

Item Type:Articles
Additional Information:This work was supported by grants awarded to C.A. Bonjardim: Fundação de Apoio a Pesquisa do Estado de Minas Gerais (FAPEMIG) - CBB – APQ-01670-11; CBB – AUC-00071-15; FAPEMIG/ PPSUS (Pesquisa Para o Serviço Único de Saúde) – CBB – APQ -04178-17.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Correa Mendonca, Dr Diogo
Authors: Valencia, H. J., de Aguiar, M. C. A. M., Costa, M. A., Mendonça, D. C., Reis, E. V., Arias, N. E. C., Drumond, B. P., and Bonjardim, C. A.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
Journal Name:Archives of Virology
Publisher:Springer
ISSN:0304-8608
ISSN (Online):1432-8798
Published Online:08 March 2021

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