The multi-targeted kinase inhibitor sunitinib and the EGFR tyrosine kinase inhibitor erlotinib, which potently bind to AAK1 and GAK (dissociation constant [KD] of 11 and 3.1 nM, respectively) (48), were shown to block HCV assembly and inhibit HCV entry with overexpression of AAK1 or GAK effectively reversing their antiviral activity (41) (42). Sunitinib and erlotinib also exhibited broad spectrum activity against dengue, West Nile virus and Zika virus infection in vitro at μM concentrations that were nontoxic to cells (46). To confirm antiviral activity of sunitinib and erlotinib, levels of phospho-AP2, a substrate of AAK1 and GAK, were measured and were found to be reduced in a dose-dependent fashion (46). Genetic (siRNA) depletion of AXL, KIT, and RET, out of a total of 27 protein targets of sunitinib and erlotinib, were found to inhibit dengue infection in a cell-based assay (46). This suggests that these three proteins are potential host targets mediating antiviral effects of the two drugs. Synergy between sunitinib and erlotinib was observed in a murine model of dengue, with 30-60 mg/kg of the drugs administered (doses chosen were at or near the approved human dose) (46). Sunitinib showed some efficacy in this model as a single agent (46). The protective effects of the combination of sunitinib and erlotinib observed in this murine model suggest it is plausible to utilize tolerable drug dosages with the potential to inhibit viral replication (46). It has been suggested, however, that side effects associated with these agents at doses required to inhibit AAK1 may not be tolerated by patients infected with SARS-CoV-2 (45).