Altiratinib blocks Toxoplasma gondii and Plasmodium falciparum development by selectively targeting a spliceosome kinase
2022
Swale, Christopher | Bellini, Valeria | Bowler, Matthew | Flore, Nardella | Brenier-Pinchart, Marie-Pierre | Cannella, Dominique | Belmudes, Lucid | Mas, Caroline | Couté, Yohann | Laurent, Fabrice | Scherf, Artur | Bougdour, Alexandre | Hakimi, Mohamed-Ali | Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB) ; Centre Hospitalier Universitaire [CHU Grenoble] (CHUGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA) | European Molecular Biology Laboratory [Grenoble] (EMBL) | Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions ; Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité) | BioSanté (UMR BioSanté) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG) ; Direction de Recherche Fondamentale (CEA) (DRF (CEA)) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA) | Integrated Structural Biology Grenoble (ISBG) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA) | Infectiologie et Santé Publique (ISP) ; Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) | Fondation pour la Recherche Medicale (EQU202103012571), Roux-Cantarini Fellowship, | ANR-11-LABX-0024,ParaFrap,Alliance française contre les maladies parasitaires(2011) | ANR-18-CE15-0023,HostQuest,Stratégies de Persistence de Toxoplasma gondii : Conquérir la Cellule Hôte et Echapper à la Réponse Immune Innée(2018) | ANR-21-CE35-0010,ApiNewDrug,Identification de nouvelles cibles thérapeutiques parmi des médicaments repositionnables pour traiter des maladies dues à des parasitaire apicomplexes(2021) | ANR-20-CE18-0006,EpiKillMal,Cibler la méthylation de l'ADN pour contrer la chimiorésistance du paludisme(2020) | ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010) | ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017) | European Project: 614880,Hosting Toxo
International audience
Mostrar más [+] Menos [-]Inglés. The Apicomplexa comprise a large phylum of single-celled, obligate intracellular protozoa that include Toxoplasma gondii , Plasmodium , and Cryptosporidium spp., which infect humans and animals and cause severe parasitic diseases. Available therapeutics against these diseases are limited by suboptimal efficacy and frequent side effects, as well as the emergence and spread of resistance. We use a drug repurposing strategy and identify altiratinib, a compound originally developed to treat glioblastoma, as a promising drug candidate with broad spectrum activity against apicomplexans. Altiratinib is parasiticidal and blocks the development of intracellular zoites in the nanomolar range and with a high selectivity index when used against T. gondii . We have identified Tg PRP4K of T. gondii as the primary target of altiratinib using genetic target deconvolution, which highlighted key residues within the kinase catalytic site that conferred drug resistance when mutated. We have further elucidated the molecular basis of the inhibitory mechanism and species selectivity of altiratinib for Tg PRP4K and for its Plasmodium falciparum counterpart, Pf CLK3. Our data identified structural features critical for binding of the other Pf CLK3 inhibitor, TCMDC-135051. Consistent with the splicing control activity of this kinase family, we have shown that altiratinib can cause global disruption of splicing, primarily through intron retention in both T. gondii and P. falciparum . Thus, our data establish parasitic PRP4K/CLK3 as a potential pan-apicomplexan target whose repertoire of inhibitors can be expanded by the addition of altiratinib.
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