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An image-based high-content screening for compounds targeting Toxoplasma gondii repurposed inhibitors effective against the malaria parasite Plasmodium falciparum.
Honfozo, Ariane; Houngue, Rodrigue; Vandeputte, Alexandre; Dechavanne, Sébastien; Nouatin, Odilon; Atindehou, Ménonvè Cynthia; Fanou, Lucie Ayi; Massougbodji, Achille; Dechavanne, Célia; Brodin, Priscille; Tomavo, Stanislas.
Afiliación
  • Honfozo A; Université Paris Saclay, CNRS UMR 9198-CEA, Institute for Integrative Biology of the Cell (I2BC), Gif sur Yvette, France.
  • Houngue R; Université Paris Saclay, CNRS UMR 9198-CEA, Institute for Integrative Biology of the Cell (I2BC), Gif sur Yvette, France.
  • Vandeputte A; Université de Lille, CNRS UMR 9017, INSERM U 1019, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, CIIL - Center for Immunity and Infection of Lille, Lille, France.
  • Dechavanne S; Université de Paris Cité, IRD, MERIT, Paris, France.
  • Nouatin O; CERPAGE, Cotonou, Benin.
  • Atindehou MC; Institut de Recherche Clinique du Bénin, Abomey-Calavi, Benin.
  • Fanou LA; Laboratoire de Biochimie et de Biologie Moléculaire, FAST/UAC, Cotonou, Benin.
  • Massougbodji A; Laboratoire de Biochimie et de Biologie Moléculaire, FAST/UAC, Cotonou, Benin.
  • Dechavanne C; Institut de Recherche Clinique du Bénin, Abomey-Calavi, Benin.
  • Brodin P; Université de Paris Cité, IRD, MERIT, Paris, France.
  • Tomavo S; CERPAGE, Cotonou, Benin.
Front Cell Infect Microbiol ; 13: 1102551, 2023.
Article en En | MEDLINE | ID: mdl-36936758
Apicomplexa phylum includes numerous obligate intracellular protozoan parasites that are life threatening for humans and animals. In this context, Plasmodium falciparum and Toxoplasma gondii are of particular interest, as they are responsible for malaria and toxoplasmosis, respectively, for which efficient vaccines are presently lacking and therapies need to be improved. Apicomplexan parasites have a highly polarized morphology, with their apical end containing specific secretory organelles named rhoptries and micronemes, which depend on the unique receptor and transporter sortilin TgSORT for their biogenesis. In the present study, we took advantage of the subcellular polarity of the parasite to engineer a clonal transgenic Toxoplasma line that expresses simultaneously the green fluorescent protein TgSORT-GFP in the post-Golgi-endosome-like compartment and the red fluorescent protein rhoptry ROP1-mCherry near the apical end. We utilized this fluorescent transgenic T. gondii to develop a miniaturized image-based phenotype assay coupled to an automated image analysis. By applying this methodology to 1,120 compounds, we identified 12 that are capable of disrupting the T. gondii morphology and inhibiting intracellular replication. Analysis of the selected compounds confirmed that all 12 are kinase inhibitors and intramembrane pumps, with some exhibiting potent activity against Plasmodium falciparum. Our findings highlight the advantage of comparative and targeted phenotypic analysis involving two related parasite species as a means of identifying molecules with a conserved mode of action.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Parásitos / Toxoplasma Tipo de estudio: Diagnostic_studies / Prognostic_studies / Screening_studies Límite: Animals / Humans Idioma: En Revista: Front Cell Infect Microbiol Año: 2023 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Suiza
Texto completo
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Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Parásitos / Toxoplasma Tipo de estudio: Diagnostic_studies / Prognostic_studies / Screening_studies Límite: Animals / Humans Idioma: En Revista: Front Cell Infect Microbiol Año: 2023 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Suiza