There is an urgent need for antiviral strategies to combat hundreds of human disease-causing viruses. Currently approved antiviral drugs treat fewer than ten viral infections. A majority of these drugs are direct-acting antivirals (DAAs) that target proteins encoded by individual viruses. As such, this approach provides a narrow spectrum of coverage and therefore cannot address the large clinical need. The high average cost (over two billion dollars) and long timeline (8–12 years) to develop a new drug (Tufts center for the Study of Drug Development, 2014), further limit the scalability of the DAA approach to drug development, particularly with respect to emerging viruses. Lastly, the inability to provide adequate global health protection and national security preparedness against newly emerging viruses and the emergence of viral resistance further challenge conventional DAAs.
The host-targeted broad-spectrum antiviral strategy represents an attractive potential solution to overcome these limitations. Viruses are dependent on cellular proteins for each step of their life cycle. Targeting host proteins required by multiple viruses can thus provide a broad-spectrum coverage with a possible added benefit of a high genetic barrier to resistance. Moreover, a broad-spectrum therapeutic could be administered even before a viral threat has been accurately diagnosed, thereby increasing protection.
Host kinase inhibitors represent one category of compounds with a great potential to be repurposed as broad-spectrum antivirals. Viruses hijack a large number of host kinases at distinct steps of their life cycle (Supekova et al., 2008; Li et al., 2009; Keating and Striker, 2012; Jiang et al., 2014). Some of these host kinases are broadly required and thus represent attractive targets for broad-spectrum therapy (Table 1 and Figure 1). These findings, combined with the development and approval of a large number of kinase inhibitors for the treatment of cancer (Gross et al., 2015) and inflammatory conditions (Ott and Adams, 2011) have sparked efforts aimed to determine the therapeutic potential of such drugs to combat viral infections. In this review, we summarize recent efforts to determine the therapeutic potential and biological rationale of repurposing already approved kinase inhibitors as antivirals.
Summary and Perspectives
While repurposing of approved drugs as host-targeted broad-spectrum antivirals offers several important advantages over development of new DAAs, it also raises concerns. One obvious concern when targeting host functions is toxicity. Nevertheless, the protective effect of sunitinib/erlotinib combinations in murine models of DENV and EBOV (Bekerman et al., 2017) suggests that for some drugs it may be feasible to find a therapeutic window where the drug level is sufficient to inhibit viral replication with minimal cellular toxicity. Shortening the duration of therapy from months or years required to treat cancer to several days sufficient to treat most acute viral infections should further limit toxicity.
Emergence of viral resistance is another potential challenge of broad-spectrum antiviral drugs (de Wispelaere et al., 2013; Haqqani and Tilton, 2013). Nevertheless, targeting host kinases that are not under the genetic control of viruses is more likely to have a higher barrier to resistance than classical DAAs. Moreover, simultaneous inhibition of several kinases or pathways by the same drug or drug combination could increase the effectiveness while minimizing viral resistance, as previously shown in cancer (Knight et al., 2010). Indeed, while DENV overcame inhibition by a DAA with the emergence of a resistance mutation, it remained susceptible to sunitinib and erlotinib, supporting the higher genetic barrier of the host-targeted antiviral approach (Bekerman et al., 2017).
Lastly, understanding the MOA is challenging since cellular kinase function in a complex network of interactions and their inhibitors are often not selective. For example, erlotinib's effect on HCV entry was first attributed solely to its effect on EGFR, its known cancer target (Lupberger et al., 2011; Diao et al., 2012). We later demonstrated that ectopic expression not only of EGFR, but also GAK, which is inhibited by erlotinib with a comparable potency to EGFR (Kd of 3.4 nM vs. 1 nM) (Karaman et al., 2008), reversed erlotinib's anti-HCV effect (Neveu et al., 2015).
Similarly, the anti-DENV effect of dasatinib was attributed to the inhibition of SFKs, particularly Fyn (Chu and Yang, 2007) (de Wispelaere et al., 2013). Nevertheless, the finding that c-Abl, another dasatinib target, is essential for DENV infection (Clark et al., 2016) suggests that c-Abl inhibition likely represents yet another mechanism through which dasatinib mediates its antiviral activity. These examples underscore the importance of validating not only the antiviral targets but also the molecular targets underlying the antiviral effect of such inhibitors.
In summary, these examples provide a proof-of-concept for the potential feasibility of repurposing of approved kinase inhibitors as host-targeted broad-spectrum antiviral therapies to combat viral infections. While not yet approved, compounds targeting other kinases, such as the phosphatidylinositol 4-kinase family and IκB kinase-α, have already demonstrated antiviral activity (Altan-Bonnet and Balla, 2012; Li et al., 2013), suggesting that the repertoire of kinase inhibitor classes available for repurposing is likely to grow. Such approaches may find utility in combination with other strategies being developed to combat viruses.
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