In vitro activity, safety and in vivo efficacy of the novel bumped kinase inhibitor BKI-1748 in non-pregnant and pregnant mice experimentally infected with Neospora caninum tachyzoites and Toxoplasma gondii oocysts. (August 2021)

• Record Type: Journal Article
• Authors: Imhof, Dennis; Anghel, Nicoleta; Winzer, Pablo; Balmer, Vreni; Ramseier, Jessica; Hänggeli, Kai; Choi, Ryan; Hulverson, Matthew A.; Whitman, Grant R.; Arnold, Samuel L.M.; Ojo, Kayode K.; Van Voorhis, Wesley C.; Doggett, J. Stone; Ortega-Mora, Luis M.; Hemphill, Andrew
• Is Part Of: International journal for parasitology. Volume 16(2021)
• Page Start: 90
• Page End: 101
• Publication Date: 2021-08
• Subjects: Bumped kinase inhibitors -- Calcium dependent protein kinase inhibitor -- Neosporosis -- Toxoplasmosis -- Pregnancy -- Tachyzoites -- Oocysts -- Treatment; Parasitic diseases -- Chemotherapy -- Periodicals; Drug resistance -- Periodicals; 616.96061
• DOI: 10.1016/j.ijpddr.2021.05.001
• Languages: English
• ISSNs: 2211-3207

Abstract

Abstract: Bumped kinase inhibitors (BKIs) target the apicomplexan calcium-dependent protein kinase 1 (CDPK1). BKI-1748, a 5-aminopyrazole-4-carboxamide compound when added to fibroblast cells concomitantly to the time of infection, inhibited proliferation of apicomplexan parasites at EC50 s of 165 nM ( Neospora caninum) and 43 nM ( Toxoplasma gondii) . Immunofluorescence and electron microscopy showed that addition of 2.5 μM BKI-1748 to infected HFF monolayers transformed parasites into multinucleated schizont-like complexes (MNCs) containing newly formed zoites, which were unable to separate and form infective tachyzoites or undergo egress. In zebrafish ( Danio rerio ) embryo development assays, no embryonic impairment was detected within 96 h at BKI-1748 concentrations up to 10 μM. In pregnant mice, BKI-1748 applied at days 9–13 of pregnancy at a dose of 20 mg/kg/day was safe and no pregnancy interference was observed. The efficacy of BKI-1748 was assessed in standardized pregnant mouse models infected with N. caninum (NcSpain-7) tachyzoites or T. gondii (TgShSp1) oocysts. In both models, treatments resulted in increased pup survival and profound inhibition of vertical transmission. However, in dams and non-pregnant mice, BKI-1748 treatments resulted in significantly decreased cerebral parasite loads only in T. gondii infected mice. In the T. gondii -model, ocular infection was detected in 10 out of 12 adult mice of the control group, but only in 3 out of 12 mice in the BKI-1748-treated group. Thus, TgShSp1 oocyst infection is a suitable model to study both cerebral and ocular infection by T. gondii. BKI-1748 represents an interesting candidate for follow-up studies on neosporosis and toxoplasmosis in larger animal models. Graphical abstract: Image 1