{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:34:17Z","timestamp":1790645657287,"version":"4.1.0"},"reference-count":47,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"656","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2022,8,3]]},"abstract":"<jats:p>\n            The Apicomplexa comprise a large phylum of single-celled, obligate intracellular protozoa that include\n            <jats:italic>Toxoplasma gondii<\/jats:italic>\n            ,\n            <jats:italic>Plasmodium<\/jats:italic>\n            , and\n            <jats:italic>Cryptosporidium<\/jats:italic>\n            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\n            <jats:italic>T. gondii<\/jats:italic>\n            . We have identified\n            <jats:italic>Tg<\/jats:italic>\n            PRP4K of\n            <jats:italic>T. gondii<\/jats:italic>\n            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\n            <jats:italic>Tg<\/jats:italic>\n            PRP4K and for its\n            <jats:italic>Plasmodium falciparum<\/jats:italic>\n            counterpart,\n            <jats:italic>Pf<\/jats:italic>\n            CLK3. Our data identified structural features critical for binding of the other\n            <jats:italic>Pf<\/jats:italic>\n            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\n            <jats:italic>T. gondii<\/jats:italic>\n            and\n            <jats:italic>P. falciparum<\/jats:italic>\n            . 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.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.abn3231","type":"journal-article","created":{"date-parts":[[2022,8,3]],"date-time":"2022-08-03T17:56:13Z","timestamp":1659549373000},"source":"Crossref","is-referenced-by-count":28,"title":["Altiratinib blocks\n            <i>Toxoplasma gondii<\/i>\n            and\n            <i>Plasmodium falciparum<\/i>\n            development by selectively targeting a spliceosome kinase"],"prefix":"10.1126","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9739-7774","authenticated-orcid":true,"given":"Christopher","family":"Swale","sequence":"first","affiliation":[{"name":"Institute for Advanced Biosciences (IAB), Team Host-Pathogen Interactions and Immunity to Infection, INSERM U1209, CNRS UMR5309, University Grenoble Alpes, Grenoble, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2066-9206","authenticated-orcid":true,"given":"Valeria","family":"Bellini","sequence":"additional","affiliation":[{"name":"Institute for Advanced Biosciences (IAB), Team Host-Pathogen Interactions and Immunity to Infection, INSERM U1209, CNRS UMR5309, University Grenoble Alpes, Grenoble, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0465-3351","authenticated-orcid":true,"given":"Matthew W.","family":"Bowler","sequence":"additional","affiliation":[{"name":"European Molecular Biology Laboratory, Grenoble, 71 Avenue des Martyrs, CS 90181, 38042 Grenoble, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3811-1633","authenticated-orcid":true,"given":"Nardella","family":"Flore","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 de Paris, Unit\u00e9 de Biologie des Interactions H\u00f4te-Parasite, CNRS ERL 9195, INSERM U1201, F-75015 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1366-5856","authenticated-orcid":true,"given":"Marie-Pierre","family":"Brenier-Pinchart","sequence":"additional","affiliation":[{"name":"Institute for Advanced Biosciences (IAB), Team Host-Pathogen Interactions and Immunity to Infection, INSERM U1209, CNRS UMR5309, University Grenoble Alpes, Grenoble, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Cannella","sequence":"additional","affiliation":[{"name":"Institute for Advanced Biosciences (IAB), Team Host-Pathogen Interactions and Immunity to Infection, INSERM U1209, CNRS UMR5309, University Grenoble Alpes, Grenoble, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3515-0055","authenticated-orcid":true,"given":"Lucid","family":"Belmudes","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Grenoble Alpes, INSERM, CEA, UMR BioSant\u00e9 U1292, CNRS, CEA, FR2048, 38000, Grenoble, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7733-6982","authenticated-orcid":true,"given":"Caroline","family":"Mas","sequence":"additional","affiliation":[{"name":"Integrated Structural Biology Grenoble (ISBG) CNRS, CEA, Universit\u00e9 Grenoble Alpes, EMBL, 71 avenue des Martyrs, F-38042, Grenoble, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3896-6196","authenticated-orcid":true,"given":"Yohann","family":"Cout\u00e9","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Grenoble Alpes, INSERM, CEA, UMR BioSant\u00e9 U1292, CNRS, CEA, FR2048, 38000, Grenoble, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9687-7952","authenticated-orcid":true,"given":"Fabrice","family":"Laurent","sequence":"additional","affiliation":[{"name":"INRAE, Universit\u00e9 Fran\u00e7ois Rabelais de Tours, Centre Val de Loire, UMR1282 ISP, Laboratoire Apicomplexes et Immunit\u00e9 Mucosale, 37380 Nouzilly, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2411-3328","authenticated-orcid":true,"given":"Artur","family":"Scherf","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 de Paris, Unit\u00e9 de Biologie des Interactions H\u00f4te-Parasite, CNRS ERL 9195, INSERM U1201, F-75015 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5895-0020","authenticated-orcid":true,"given":"Alexandre","family":"Bougdour","sequence":"additional","affiliation":[{"name":"Institute for Advanced Biosciences (IAB), Team Host-Pathogen Interactions and Immunity to Infection, INSERM U1209, CNRS UMR5309, University Grenoble Alpes, Grenoble, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2547-8233","authenticated-orcid":true,"given":"Mohamed-Ali","family":"Hakimi","sequence":"additional","affiliation":[{"name":"Institute for Advanced Biosciences (IAB), Team Host-Pathogen Interactions and Immunity to Infection, INSERM U1209, CNRS UMR5309, University Grenoble Alpes, Grenoble, France."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_3_2_2","unstructured":"World Health Organization World Malaria Report 2021 (World Health Organization 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