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

Abstract

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-α/β and IFN-γ 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.

Baricitinib as potential treatment for 2019-nCoV acute respiratory disease

“…These included a number of oncology drugs such as sunitinib and erlotinib, both of which have been shown to inhibit viral infection of cells through the inhibition of AAK1. 5 However, these compounds bring serious side-effects, and our data infer high doses to inhibit AAK1 effectively. We do not consider these drugs would be a safe therapy for a population of sick and infected people.…”

COVID-19: combining antiviral and anti-inflammatory treatments

“…The drug targets are members of the numbassociated kinase (NAK) family-including AAK1 and GAK-the inhibition of which has been shown to reduce viral infection in vitro. 5,6 Baricitinib was identified as a NAK inhibitor, with a particularly high affinity for AAK1, a pivotal regulator of clathrin-mediated endocytosis. We suggested that this drug could be of use in countering SARS-CoV-2 infections, subject to appropriate clinical testing.…”

“…Other AI-algorithm-predicted NAK inhibitors include a combination of the oncology drugs sunitinib and erlotinib, shown to reduce the infectivity of a wide range of viruses, including hepatitis C virus, dengue virus, Ebola virus, and respiratory syncytial virus. 5,6 However, sunitinib and erlotinib would be difficult for patients to tolerate at the doses required to inhibit AAK1 and GAK. By contrast, at therapeutic doses used for the treatment of patients with rheumatoid arthritis, the free plasma concentrations of baricitinib are predicted to be sufficient to inhibit AAK1, and potentially GAK, in cellbased assays.…”

Drug repurposing for new, efficient, broad spectrum antivirals

“…Erlotinib, another anticancer drug, also inhibits HCV entry and assembly. Similarly, sunitinib and/or erlotinib can restrict infection by DENV and EBOV in vitro and in a murine animal model and have potent in vitro antiviral activity against ZIKV, WNV, CHIKV, Junin virus (JUNV) and respiratory syncytial virus (RSV) (Bekerman et al, 2017;Pu et al, 2018). Sunitinib has also been shown to inhibit HCMV infection in cell culture (Cai et al, 2014) and HIV-1 infection of resting CD4 T cells (Guo et al, 2013).…”