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.

Synergism between the tyrosine kinase inhibitor sunitinib and Anti-TNF antibody protects against lethal dengue infection

“…Our results thus confirm and extend the published finding by demonstrating that sunitinib and anti-TNF acted synergistically to improve survival without affecting tissue viral burden. This is consistent with studies showing that sunitinib or anti-TNF treatment alone had no effects on viremia (Bekerman et al, 2017; Phanthanawiboon et al, 2016). In addition to the known effects of sunitinib on angiogenesis and vascular permeability (Hofmann et al, 2002; Inyoo et al, 2017; Marzola et al, 2005), TNF blockade alone has been shown to decrease vascular leakage in DENV-infected mice (Ng et al, 2014; Watanabe et al, 2015).…”

Novel activities of safe-in-human broad-spectrum antiviral agents

“…Anti-malaria quinolones (chloroquine and hydroxychloroquine) inhibit acidification of endosomes, which is an essential process for uncoating of ssRNA viruses (Al-Bari, 2017). Anticancer kinase inhibitors dasatinib, imatinib, gefitinib, nilotinib, erlotinib and sunitinib impair intracellular viral trafficking and exert BSA effects (Bekerman et al, 2017;Schor and Einav, 2018). The anti-Duchenne muscular dystrophy agent, alisporivir, targets cellular cyclophilin and inhibits the folding of HCV, HIV, MERS-and SARS-CoV proteins, and, therefore, prevents formation of infectious virus particles (Boldescu et al, 2017;de Wilde et al, 2017;Soriano et al, 2011).…”

A Scaffold‐Hopping Strategy toward the Identification of Inhibitors of Cyclin G Associated Kinase

“…While GAK‐dependent phosphorylation of AP2 is important for its endocytic activity, GAK′s phosphorylation of AP1 is implicated in trans‐Golgi network (TGN)‐to‐lysosome trafficking. This phosphorylation of APs enhances their binding to cargo proteins and helps the recruitment of clathrin to the membrane to form a clathrin‐coated vesicle (CCV) . In analogy to auxilin I, GAK contains a C‐terminal J‐domain that acts as a co‐chaperone with the heat shock cognate 71 kDa protein (HSC70) to uncoat CCVs in order to recycle clathrin back to the cell surface .…”