Treatment with the novel bumped kinase inhibitor BKI-1748 confers protection against congenital toxoplasmosis in sheep

SÁNCHEZ-SÁNCHEZ, ROBERTO; IMHOF, DENNIS; HECKER Y.P.; FERRE, IGNACIO; RE, MICHELA; MORENO-GONZALO, JAVIER; MEJÍAS-LÓPEZ, ELENA; MANUEL PIZARRO-DÍAZ; EDGAR GUILLERMO VALDIVIA- LARA; MATTHEW A. HULVERSON; RYAN CHOI; ERKANG FAN; ANDREW HEMPHILL; WESLEY C. VAN VOORHIS; ORTEGA-MORA L.M.

Berna

Congreso; 6th International Meeting on Apicomplexan Parasites in Farm Animals; 2022

ApicoWplexa network

Congenital Toxoplasma gondii infection in humans and in some mammal species, such as smallruminants, is a well-known cause of abortion and fetal malformations. First-line antifolate therapy has a high rate of adverse effects, such as hematologic toxicity and allergic reactions, that compromise their use for prophylactic and therapeutic treatments. Therefore, it is of great importance to identify novel dual-use candidates that would be well-tolerated in humans and animals. Calcium-dependent protein kinase 1 (CDPK1) represents a promising drug target. Bumped kinase inhibitors (BKIs) specifically inhibit the activity of CDPK1. In previous studies using a congenital model of ovine toxoplasmosis, treatment with BKI-1294 conferred a reduction of 71% in abortions and 53% in the vertical transmission of the parasite. However, BKI-1294 has some drawbacks, such as the inhibition of hERG (human ethera-go-go related gene), that exclude its use in humans. Recently, the newly developed BKI-1748 displayed excellent safety and efficacy features in vitro (parasitostatic effect) and in mice models of T. gondii infection. The aim of this work was to investigate the efficacy of BKI-1748 in a congenital model of ovine toxoplasmosis. Eighteen pregnant sheep were distributed in three experimental groups. Group 1 (G1, n=7) and group 2 (G2, n=8) were dosed orally with 1,000 T. gondii sporulated oocysts at 90 days of gestation (dg). Animals from group 3 (G3, n=3) were mock dosed with PBS at 90 dg. Beginning 48 hours post infection, BKI-1748 was administered orally to G1 at 15 mg/kg, 10 doses every other day. Maximum plasma drug concentrations (Cmax) of 2-5 μM were reached at 12 hours after each BKI-1748 dose. In addition, BKI-1748 was found in fetal plasma samples (Cmax of 0.5 μM at 20 hours after treatment). Rectal temperatures were significantly lower in G1 than in G2 between days 5 and 10 pi while in G3 they were in the physiological range throughout the study. All sheep from G2 aborted. By contrast, all sheep from G1 and G3 gave birth to healthy lambs. While all sheep from G2 showed seroconversion, none of the sheep from G1 and G3 seroconverted. Finally, parasite DNA was not detected in cotyledons nor target tissues from the lambs in G1. Therefore, results obtained here demonstrate that BKI-1748 confers protection against congenital toxoplasmosis in sheep. Future studies would be important to investigate the efficacy of this compound using different dose regimes and/or different infection doses before testing its efficacy in field trials.