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.

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 (2021). 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. International journal for parasitology. Drugs and drug resistance, 16, pp. 90-101. Elsevier 10.1016/j.ijpddr.2021.05.001

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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 EC50s 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Parasitology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Imhof, Dennis; Anghel, Nicoleta; Winzer, Pablo Arnold; Balmer, Vreni; Ramseier, Jessica; Hänggeli, Kai Pascal Alexander and Hemphill, Andrew

Subjects:

600 Technology > 630 Agriculture
500 Science
500 Science > 570 Life sciences; biology

ISSN:

2211-3207

Publisher:

Elsevier

Language:

English

Submitter:

Andrew Hemphill

Date Deposited:

29 Oct 2021 15:41

Last Modified:

29 Oct 2021 15:41

Publisher DOI:

10.1016/j.ijpddr.2021.05.001

PubMed ID:

34030110

Uncontrolled Keywords:

Bumped kinase inhibitors Calcium dependent protein kinase inhibitor Neosporosis Oocysts Pregnancy Tachyzoites Toxoplasmosis Treatment

BORIS DOI:

10.48350/160250

URI:

https://boris.unibe.ch/id/eprint/160250

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