Targeting filarial Abl-like kinases: Orally available, food and drug administration-approved tyrosine kinase inhibitors are microfilaricidal and macrofilaricidal

Abstract

Background: Elimination of onchocerciasis and lymphatic filariasis is targeted for 2020. Given the coincident Loa loa infections in Central Africa and the potential for drug resistance development, the need for new microfilaricides and macrofilaricides has never been greater. With the genomes of L. loa, Onchocerca volvulus, Wuchereria bancrofti, and Brugia malayi available, new drug targets have been identified. Methods: The effects of the tyrosine kinase inhibitors imatinib, nilotinib, and dasatinib on B. malayi adult males, adult females, L3 larvae, and microfilariae were assessed using a wide dose range (0-100 μM) in vitro. Results: For microfilariae, median inhibitory concentrations (IC50 values) on day 6 were 6.06 μM for imatinib, 3.72 μM for dasatinib, and 81.35 μM for nilotinib; for L3 larvae, 11.27 μM, 13.64 μM, and 70.98 μM, respectively; for adult males, 41.6 μM, 3.87 μM, and 68.22 μM, respectively; and for adult females, 42.89 μM, 9.8 μM, and >100 μM, respectively. Three-dimensional modeling suggests how these tyrosine kinase inhibitors bind and inhibit filarial protein activity. Conclusions: Given the safety of imatinib in humans, plans are underway for pilot clinical trials to assess its efficacy in patients with filarial infections.