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Sánchez-Sánchez, Roberto; Imhof, Dennis; Hecker, Yanina P; Ferre, Ignacio; Re, Michela; Moreno-Gonzalo, Javier; Blanco-Murcia, Javier; Mejías-López, Elena; Hulverson, Matthew A; Choi, Ryan; Arnold, Samuel L M; Ojo, Kayode K; Barrett, Lynn K; Hemphill, Andrew; Van Voorhis, Wesley C; Ortega-Mora, Luis Miguel
The Journal of infectious diseases, 02/2024, Letnik: 229, Številka: 2Journal Article
Abstract Congenital toxoplasmosis in humans and in other mammalian species, such as small ruminants, is a well-known cause of abortion and fetal malformations. The calcium-dependent protein kinase 1 (CDPK1) inhibitor BKI-1748 has shown a promising safety profile for its use in humans and a good efficacy against Toxoplasma gondii infection in vitro and in mouse models. Ten doses of BKI-1748 given every other day orally in sheep at 15 mg/kg did not show systemic or pregnancy-related toxicity. In sheep experimentally infected at 90 days of pregnancy with 1000 TgShSp1 oocysts, the BKI-1748 treatment administered from 48 hours after infection led to complete protection against abortion and congenital infection. In addition, compared to infected/untreated sheep, treated sheep showed a drastically lower rectal temperature increase and none showed IgG seroconversion throughout the study. In conclusion, BKI-1748 treatment in pregnant sheep starting at 48 hours after infection was fully effective against congenital toxoplasmosis. Toxoplasmosis is a zoonotic disease and the first-line treatments for congenital Toxoplasma gondii infections in humans lack sufficient safety and efficacy. BKI-1748 is a lead compound and here we demonstrate its favorable safety and efficacy in sheep.
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