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The small molecule AZD6244 inhibits dengue virus replication in vitro and protects against lethal challenge in a mouse model

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Abstract

Dengue virus (DENV) is the most common mosquito-borne viral disease. The World Health Organization estimates that 400 million new cases of dengue fever occur every year. Approximately 500,000 individuals develop severe and life-threatening complications from dengue fever, such as dengue shock syndrome (DSS) and dengue hemorrhagic fever (DHF), which cause 22,000 deaths yearly. Currently, there are no specific licensed therapeutics to treat DENV illness. We have previously shown that the MEK/ERK inhibitor U0126 inhibits the replication of the flavivirus yellow fever virus. In this study, we demonstrate that the MEK/ERK inhibitor AZD6244 has potent antiviral efficacy in vitro against DENV-2, DENV-3, and Saint Louis encephalitis virus (SLEV). We also show that it is able to protect AG129 mice from a lethal challenge with DENV-2 (D2S20). The molecule is currently undergoing phase III clinical trials for the treatment of non-small-cell lung cancer. The effect of AZD6244 on the DENV life cycle was attributed to a blockade of morphogenesis. Treatment of AG129 mice twice daily with oral doses of AZD6244 (100 mg/kg/day) prevented the animals from contracting dengue hemorrhagic fever (DHF)-like lethal disease upon intravenous infection with 1 × 105 PFU of D2S20. The effectiveness of AZD6244 was observed even when the treatment of infected animals was initiated 1-2 days postinfection. This was also followed by a reduction in viral copy number in both the serum and the spleen. There was also an increase in IL-1β and TNF-α levels in mice that were infected with D2S20 and treated with AZD6244 in comparison to infected mice that were treated with the vehicle only. These data demonstrate the potential of AZD6244 as a new therapeutic agent to treat DENV infection and possibly other flavivirus diseases.

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Acknowledgements

The authors are grateful to Dr. Michael S. Diamond, Washington University, St. Louis, MO, USA, for providing us with the AG129 mice. We also thank Dr. Erna G. Kroon from Laboratório de Virus – UFMG for the kind gift of DENV-2 and -3 viruses, and Dr. Maurício L. Nogueira from FAMERP – SJRP - SP, Brazil, for the gift of SLEV. This work was supported by grants awarded to CAB from FAPEMIG - CBB – APQ-01670-11; CBB – AUC-00071-15; CAPES – AUXPE/PROEX/2015; CNPq - 476288/2012-6; FAPEMIG/PPSUS – CBB – APQ -04178-17.

Funding

FAPEMIG - CBB – APQ-01670-11; CBB – AUC-00071-15; CAPES – AUXPE/PROEX/2015; CNPq - 476288/2012-6; FAPEMIG/PPSUS – CBB – APQ -04178-17.

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Author notes

  1. Jonas D. Albarnaz & Alice A. Torres

    Present address: Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK

  2. Leonardo C. de Oliveira and Aryádina M. Ribeiro contributed equally to this study.

Authors and Affiliations

  1. Grupo de Transdução de Sinal/Flavivírus, Laboratório de Vírus, Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, Campus Pampulha, Belo Horizonte, MG, 31270-901, Brazil

    Leonardo C. de Oliveira, Aryádina M. Ribeiro, Jonas D. Albarnaz, Alice A. Torres, Luís F. Z. Guimarães & Cláudio A. Bonjardim

  2. Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, USA

    Leonardo C. de Oliveira, Aryádina M. Ribeiro, Amelia K. Pinto, Scott Parker, Konstantin Doronin, James D. Brien & Mark R. Buller

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  1. Leonardo C. de Oliveira
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Correspondence to Cláudio A. Bonjardim.

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Animal Care and Use Committee at Saint Louis University (Animal Welfare Assurance: D16-00141, IACUC protocol: 2667).

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de Oliveira, L.C., Ribeiro, A.M., Albarnaz, J.D. et al. The small molecule AZD6244 inhibits dengue virus replication in vitro and protects against lethal challenge in a mouse model. Arch Virol 165, 671–681 (2020). https://doi.org/10.1007/s00705-020-04524-7

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