4.7 Article

Feasibility and biological rationale of repurposing sunitinib and erlotinib for dengue treatment

Journal

ANTIVIRAL RESEARCH
Volume 155, Issue -, Pages 67-75

Publisher

ELSEVIER SCIENCE BV
DOI: 10.1016/j.antiviral.2018.05.001

Keywords

Dengue virus; Antivirals; Kinase inhibitors; Drug repurposing; Virus-host interactions

Funding

  1. National Institute of Allergy and Infectious Diseases (NIAID) [1U19AI10966201]
  2. Stanford SPARK program
  3. Child Health Research Institute
  4. Lucile Packard Foundation for Children's Health
  5. Stanford CTSA [UL1 TR000093]

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There is an urgent need for strategies to combat dengue virus (DENV) infection; a major global threat. We reported that the cellular kinases AAK1 and GAK regulate intracellular trafficking of multiple viruses and that sunitinib and erlotinib, approved anticancer drugs with potent activity against these kinases, protect DENV-infected mice from mortality. Nevertheless, further characterization of the therapeutic potential and underlying mechanism of this approach is required prior to clinical evaluation. Here, we demonstrate that sunitinib/erlotinib combination achieves sustained suppression of systemic infection at approved dose in DENV-infected IFN alpha/beta and IFN-gamma receptor deficient mice. Nevertheless, treatment with these blood-brain barrier impermeable drugs delays, yet does not prevent, late-onset paralysis; a common manifestation in this immunodeficient mouse model but not in humans. Sunitinib and erlotinib treatment also demonstrates efficacy in human primary monocyte-derived dendritic cells. Additionally, DENV infection induces expression of AAK1 transcripts, but not GAK, via single-cell transcriptomics, and these kinases are important molecular targets underlying the anti-DENV effect of sunitinib and erlotinib. Lastly, sunitinib/erlotinib combination alters inflammatory cytokine responses in DENV-infected mice. These findings support feasibility of repurposing sunitinib/erlotinib combination as a host-targeted antiviral approach and contribute to understanding its mechanism of antiviral action.

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