Anticancer kinase inhibitors impair intracellular viral trafficking and exert broad-spectrum antiviral effects
Elena Bekerman, … , Glenn Randall, Shirit Einav
Elena Bekerman, … , Glenn Randall, Shirit Einav
Published February 27, 2017
Citation Information: J Clin Invest. 2017;127(4):1338-1352. https://doi.org/10.1172/JCI89857.
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Research Article Virology

Anticancer kinase inhibitors impair intracellular viral trafficking and exert broad-spectrum antiviral effects

Abstract

Global health is threatened by emerging viral infections, which largely lack effective vaccines or therapies. Targeting host pathways that are exploited by multiple viruses could offer broad-spectrum solutions. We previously reported that AAK1 and GAK, kinase regulators of the host adaptor proteins AP1 and AP2, are essential for hepatitis C virus (HCV) infection, but the underlying mechanism and relevance to other viruses or in vivo infections remained unknown. Here, we have discovered that AP1 and AP2 cotraffic with HCV particles in live cells. Moreover, we found that multiple viruses, including dengue and Ebola, exploit AAK1 and GAK during entry and infectious virus production. In cultured cells, treatment with sunitinib and erlotinib, approved anticancer drugs that inhibit AAK1 or GAK activity, or with more selective compounds inhibited intracellular trafficking of HCV and multiple unrelated RNA viruses with a high barrier to resistance. In murine models of dengue and Ebola infection, sunitinib/erlotinib combination protected against morbidity and mortality. We validated sunitinib- and erlotinib-mediated inhibition of AAK1 and GAK activity as an important mechanism of antiviral action. Additionally, we revealed potential roles for additional kinase targets. These findings advance our understanding of virus-host interactions and establish a proof of principle for a repurposed, host-targeted approach to combat emerging viruses.

Authors

Elena Bekerman, Gregory Neveu, Ana Shulla, Jennifer Brannan, Szu-Yuan Pu, Stanley Wang, Fei Xiao, Rina Barouch-Bentov, Russell R. Bakken, Roberto Mateo, Jennifer Govero, Claude M. Nagamine, Michael S. Diamond, Steven De Jonghe, Piet Herdewijn, John M. Dye, Glenn Randall, Shirit Einav

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Figure 5

AAK1 and GAK inhibitors are protective in murine models of dengue and Ebola.

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AAK1 and GAK inhibitors are protective in murine models of dengue and Eb...
(A) DENV viremia in AG-B6 mice measured by qRT-PCR on day 2 postinfection following once-daily administration of vehicle, sunitinib (SM), and/or erlotinib (E). (B) DENV viremia in AG-B6 mice on days 2 and 3 postinfection following twice-daily drug administration. (C and D) Weight loss (C) and mortality (D) of DENV-infected AG-B6 mice treated once daily for 5 days with vehicle or sunitinib/erlotinib combination (n = 8 per treatment group). (E) Mortality of DENV-infected AG-129 mice treated once daily for 5 days with vehicle, sunitinib, and/or erlotinib (data are pooled from 2 independent experiments, n = 8–16 per treatment group). (F) Mortality of DENV-infected AG-B6 mice treated once daily with vehicle or sunitinib/erlotinib combination beginning at the indicated hour after inoculation, T0–T48 (data are pooled from 2 independent experiments, n = 8–16 per treatment group). (G and H) Weight loss (G) and mortality (H) of EBOV-infected C57BL/6 mice treated once daily for 10 days with vehicle, sunitinib, and/or erlotinib (n = 10 per treatment group). Doses are in mg/kg. Administration was i.p., except when denoted p.o. (C and D), at inoculation (A–E, G, and H) or after inoculation (F). A–D, G, and H are representative of 2 or more independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001 relative to vehicle control by nonparametric Kruskal-Wallis test with Dunn’s multiple comparisons post-test (A) or nonparametric Mann-Whitney test (B). Survival analysis (D–F and H) was done with log-rank (Mantel-Cox) test; P values are relative to vehicle control. GE, genomic equivalents.