Repurposing ALK inhibitors as influenza and corona virus antivirals targeting lymphocyte tyrosine kinase (LTK)

Abstract

The development of effective antiviral drugs for pandemic scenarios is a significant challenge, particularly due to the rapid emergence of drug-resistant viral strains and a paucity of drugs that have broad efficacy across viral families. A promising strategy is so called host-targeted therapeutics which inhibit host-mechanisms that viruses rely on instead of viruses themselves. LTK, an endoplasmic reticulum-resident kinase, plays a crucial role in ER-to-Golgi trafficking, a process exploited by many viruses during their life cycle, and is therefore a potential candidate for host-targeted antiviral therapeutics. LTK is highly homologous to ALK, a tyrosine kinase that can be aberrantly expressed by cancer cells, and importantly, LTK, but not ALK, is expressed in the lung and small intestine. We here repurposed ALK-inhibitors that also inhibit LTK, and investigated if this inhibition could reduce viral load and serve as a new class of antiviral drug. In vitro, influenza and SARS-CoV-2 viruses could be inhibited by the LTK inhibitors ceritinib, crizotinib, entrectinib, ensartinib, brigatinib, and alectinib, but not lorlatinib. Importantly, the repurposed ALK-inhibitors crizotinib, brigatinib, and ceritinib also gave some protection in mice against lethal viral challenges with influenza and SARS-CoV-2, respectively. The study highlights the potential of LTK inhibition as target for a new class of host-targeted antivirals therapeutics.