Safety and efficacy of the bumped kinase inhibitor BKI-1553 in pregnant sheep experimentally infected with Neospora caninum tachyzoites

Sánchez Sánchez, Roberto; Ferré Pérez, Ignacio; Re, Michela Tatiana; Vázquez Arbáizar, María Patricia; Ferrer, Luis Miguel; Blanco Murcia, Francisco Javier; Regidor Cerrillo, Javier; Pizarro Díaz, Manuel; González Huecas, Marta; Tabanera De Lucio, Enrique; García Lunar, Paula; Benavides, Julio; Castaño, Pablo; Hemphill, Andrew; Hulverson, Matthew A.; Whitman, Grant R.; Rivas, Kasey L.; Choi, Ryan; Ojo, Kayode K.; Barrett, Lynn K.; Van Voorhis, Wesley C.; Ortega Mora, Luis Miguel

Safety and efficacy of the bumped kinase inhibitor BKI-1553 in pregnant sheep experimentally infected with Neospora caninum tachyzoites

Neospora caninum is one of the main causes of abortion in cattle, and recent studies have highlighted its relevance as an abortifacient in small ruminants. Vaccines or drugs for the control of neosporosis are lacking. Bumped kinase inhibitors (BKIs), which are ATP-competitive inhibitors of calcium d...

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Autores:	Sánchez Sánchez, Roberto, Ferré Pérez, Ignacio, Re, Michela Tatiana, Vázquez Arbáizar, María Patricia, Ferrer, Luis Miguel, Blanco Murcia, Francisco Javier, Regidor Cerrillo, Javier, Pizarro Díaz, Manuel, González Huecas, Marta, Tabanera De Lucio, Enrique, García Lunar, Paula, Benavides, Julio, Castaño, Pablo, Hemphill, Andrew, Hulverson, Matthew A., Whitman, Grant R., Rivas, Kasey L., Choi, Ryan, Ojo, Kayode K., Barrett, Lynn K., Van Voorhis, Wesley C., Ortega Mora, Luis Miguel
Tipo de recurso:	artículo
Fecha de publicación:	2018
País:	España
Institución:	Universidad Complutense de Madrid (UCM)
Repositorio:	Docta Complutense
Idioma:	inglés
OAI Identifier:	oai:docta.ucm.es:20.500.14352/111891
Acceso en línea:	https://hdl.handle.net/20.500.14352/111891
Access Level:	acceso abierto
Palabra clave:	636.09 Neospora caninum Sheep Pregnancy Treatment Protein kinase inhibitor BKI-1553 Ciencias Biomédicas 24 Ciencias de la Vida

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spelling	Safety and efficacy of the bumped kinase inhibitor BKI-1553 in pregnant sheep experimentally infected with Neospora caninum tachyzoitesSánchez Sánchez, RobertoFerré Pérez, IgnacioRe, Michela TatianaVázquez Arbáizar, María PatriciaFerrer, Luis MiguelBlanco Murcia, Francisco JavierRegidor Cerrillo, JavierPizarro Díaz, ManuelGonzález Huecas, MartaTabanera De Lucio, EnriqueGarcía Lunar, PaulaBenavides, JulioCastaño, PabloHemphill, AndrewHulverson, Matthew A.Whitman, Grant R.Rivas, Kasey L.Choi, RyanOjo, Kayode K.Barrett, Lynn K.Van Voorhis, Wesley C.Ortega Mora, Luis Miguel636.09Neospora caninumSheepPregnancyTreatmentProtein kinase inhibitorBKI-1553Ciencias Biomédicas24 Ciencias de la VidaNeospora caninum is one of the main causes of abortion in cattle, and recent studies have highlighted its relevance as an abortifacient in small ruminants. Vaccines or drugs for the control of neosporosis are lacking. Bumped kinase inhibitors (BKIs), which are ATP-competitive inhibitors of calcium dependent protein kinase 1 (CDPK1), were shown to be highly efficacious against several apicomplexan parasites in vitro and in laboratory animal models. We here present the pharmacokinetics, safety and efficacy of BKI-1553 in pregnant ewes and foetuses using a pregnant sheep model of N. caninum infection. BKI-1553 showed exposure in pregnant ewes with trough concentrations of approximately 4 μM, and of 1  μM in foetuses. Subcutaneous BKI-1553 administration increased rectal temperatures shortly after treatment, and resulted in dermal nodules triggering a slight monocytosis after repeated doses at short intervals. BKI-1553 treatment decreased fever in infected pregnant ewes already after two applications, resulted in a 37–50% reduction in foetal mortality, and modulated immune responses; IFNγ levels were increased early after infection and IgG levels were reduced subsequently. N. caninum was abundantly found in placental tissues; however, parasite detection in foetal brain tissue decreased from 94% in the infected/untreated group to 69–71% in the treated groups. In summary, BKI-1553 confers partial protection against abortion in a ruminant experimental model of N. caninum infection during pregnancy. In addition, reduced parasite detection, parasite load and lesions in foetal brains were observed.ElsevierUniversidad Complutense de Madrid20182018-01-0120182018-01-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/111891reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)InglésengMinisterio de Educación, Cultura y Deporte http://dx.doi.org/10.13039/501100003176 Not available MATR-FPU13%2F03438 MATR-FPU13%2F03438Ministerio de Economía y Competitividad http://dx.doi.org/10.13039/501100003329 Not available FJCI-2014-20982 FJCI-2014-20982open accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/1118912026-06-02T12:44:21Z
dc.title.none.fl_str_mv	Safety and efficacy of the bumped kinase inhibitor BKI-1553 in pregnant sheep experimentally infected with Neospora caninum tachyzoites
title	Safety and efficacy of the bumped kinase inhibitor BKI-1553 in pregnant sheep experimentally infected with Neospora caninum tachyzoites
spellingShingle	Safety and efficacy of the bumped kinase inhibitor BKI-1553 in pregnant sheep experimentally infected with Neospora caninum tachyzoites Sánchez Sánchez, Roberto 636.09 Neospora caninum Sheep Pregnancy Treatment Protein kinase inhibitor BKI-1553 Ciencias Biomédicas 24 Ciencias de la Vida
title_short	Safety and efficacy of the bumped kinase inhibitor BKI-1553 in pregnant sheep experimentally infected with Neospora caninum tachyzoites
title_full	Safety and efficacy of the bumped kinase inhibitor BKI-1553 in pregnant sheep experimentally infected with Neospora caninum tachyzoites
title_fullStr	Safety and efficacy of the bumped kinase inhibitor BKI-1553 in pregnant sheep experimentally infected with Neospora caninum tachyzoites
title_full_unstemmed	Safety and efficacy of the bumped kinase inhibitor BKI-1553 in pregnant sheep experimentally infected with Neospora caninum tachyzoites
title_sort	Safety and efficacy of the bumped kinase inhibitor BKI-1553 in pregnant sheep experimentally infected with Neospora caninum tachyzoites
dc.creator.none.fl_str_mv	Sánchez Sánchez, Roberto Ferré Pérez, Ignacio Re, Michela Tatiana Vázquez Arbáizar, María Patricia Ferrer, Luis Miguel Blanco Murcia, Francisco Javier Regidor Cerrillo, Javier Pizarro Díaz, Manuel González Huecas, Marta Tabanera De Lucio, Enrique García Lunar, Paula Benavides, Julio Castaño, Pablo Hemphill, Andrew Hulverson, Matthew A. Whitman, Grant R. Rivas, Kasey L. Choi, Ryan Ojo, Kayode K. Barrett, Lynn K. Van Voorhis, Wesley C. Ortega Mora, Luis Miguel
author	Sánchez Sánchez, Roberto
author_facet	Sánchez Sánchez, Roberto Ferré Pérez, Ignacio Re, Michela Tatiana Vázquez Arbáizar, María Patricia Ferrer, Luis Miguel Blanco Murcia, Francisco Javier Regidor Cerrillo, Javier Pizarro Díaz, Manuel González Huecas, Marta Tabanera De Lucio, Enrique García Lunar, Paula Benavides, Julio Castaño, Pablo Hemphill, Andrew Hulverson, Matthew A. Whitman, Grant R. Rivas, Kasey L. Choi, Ryan Ojo, Kayode K. Barrett, Lynn K. Van Voorhis, Wesley C. Ortega Mora, Luis Miguel
author_role	author
author2	Ferré Pérez, Ignacio Re, Michela Tatiana Vázquez Arbáizar, María Patricia Ferrer, Luis Miguel Blanco Murcia, Francisco Javier Regidor Cerrillo, Javier Pizarro Díaz, Manuel González Huecas, Marta Tabanera De Lucio, Enrique García Lunar, Paula Benavides, Julio Castaño, Pablo Hemphill, Andrew Hulverson, Matthew A. Whitman, Grant R. Rivas, Kasey L. Choi, Ryan Ojo, Kayode K. Barrett, Lynn K. Van Voorhis, Wesley C. Ortega Mora, Luis Miguel
author2_role	author author author author author author author author author author author author author author author author author author author author author
dc.contributor.none.fl_str_mv	Universidad Complutense de Madrid
dc.subject.none.fl_str_mv	636.09 Neospora caninum Sheep Pregnancy Treatment Protein kinase inhibitor BKI-1553 Ciencias Biomédicas 24 Ciencias de la Vida
topic	636.09 Neospora caninum Sheep Pregnancy Treatment Protein kinase inhibitor BKI-1553 Ciencias Biomédicas 24 Ciencias de la Vida
description	Neospora caninum is one of the main causes of abortion in cattle, and recent studies have highlighted its relevance as an abortifacient in small ruminants. Vaccines or drugs for the control of neosporosis are lacking. Bumped kinase inhibitors (BKIs), which are ATP-competitive inhibitors of calcium dependent protein kinase 1 (CDPK1), were shown to be highly efficacious against several apicomplexan parasites in vitro and in laboratory animal models. We here present the pharmacokinetics, safety and efficacy of BKI-1553 in pregnant ewes and foetuses using a pregnant sheep model of N. caninum infection. BKI-1553 showed exposure in pregnant ewes with trough concentrations of approximately 4 μM, and of 1  μM in foetuses. Subcutaneous BKI-1553 administration increased rectal temperatures shortly after treatment, and resulted in dermal nodules triggering a slight monocytosis after repeated doses at short intervals. BKI-1553 treatment decreased fever in infected pregnant ewes already after two applications, resulted in a 37–50% reduction in foetal mortality, and modulated immune responses; IFNγ levels were increased early after infection and IgG levels were reduced subsequently. N. caninum was abundantly found in placental tissues; however, parasite detection in foetal brain tissue decreased from 94% in the infected/untreated group to 69–71% in the treated groups. In summary, BKI-1553 confers partial protection against abortion in a ruminant experimental model of N. caninum infection during pregnancy. In addition, reduced parasite detection, parasite load and lesions in foetal brains were observed.
publishDate	2018
dc.date.none.fl_str_mv	2018 2018-01-01 2018 2018-01-01
dc.type.none.fl_str_mv	journal article http://purl.org/coar/resource_type/c_6501 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv	info:eu-repo/semantics/article
format	article
dc.identifier.none.fl_str_mv	https://hdl.handle.net/20.500.14352/111891
url	https://hdl.handle.net/20.500.14352/111891
dc.language.none.fl_str_mv	Inglés eng
language_invalid_str_mv	Inglés
language	eng
dc.relation.none.fl_str_mv	Ministerio de Educación, Cultura y Deporte http://dx.doi.org/10.13039/501100003176 Not available MATR-FPU13%2F03438 MATR-FPU13%2F03438 Ministerio de Economía y Competitividad http://dx.doi.org/10.13039/501100003329 Not available FJCI-2014-20982 FJCI-2014-20982
dc.rights.none.fl_str_mv	open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv	info:eu-repo/semantics/openAccess
rights_invalid_str_mv	open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.publisher.none.fl_str_mv	Elsevier
publisher.none.fl_str_mv	Elsevier
dc.source.none.fl_str_mv	reponame:Docta Complutense instname:Universidad Complutense de Madrid (UCM)
instname_str	Universidad Complutense de Madrid (UCM)
reponame_str	Docta Complutense
collection	Docta Complutense
repository.name.fl_str_mv
repository.mail.fl_str_mv
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Safety and efficacy of the bumped kinase inhibitor BKI-1553 in pregnant sheep experimentally infected with Neospora caninum tachyzoites

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