Small molecule kinase inhibitor altiratinib inhibits brain cyst forming bradyzoites of Toxoplasma gondii.

Abstract

Chronic toxoplasmosis is caused by Toxoplasma gondii bradyzoites. This study assessed six candidate small molecule kinase inhibitors (SMKIs) against bradyzoites (ME49 strain), the reactivated form of the parasite resulting from the rupture of brain cysts. Bradyzoites were obtained from mouse brain cysts, cultured in ARPE-19 cells, and treated with afatinib and neratinib (HER2/HER4 inhibitors), ACTB-1003 and regorafenib (VEGFR-2 inhibitors), or altiratinib and foretinib (c-MET inhibitors). The effects on the growth of T. gondii were analyzed by western blot and immunofluorescence assay. Changes in the host cells were assessed using markers for cell viability, apoptosis, necrosis, and autophagy. All inhibitors blocked the growth of bradyzoites, although afatinib was less effective. Afatinib enhanced autophagy signals, while ACTB-1003 and neratinib affected mitochondrial biosynthesis and mitophagy. Altiratinib demonstrated an effect against bradyzoites at the lowest concentration with minimal impact on the host cells. It may be effective in blocking the reactivation of brain cysts in immunodeficiency patients caused by bradyzoites.