Altiratinib blocks Toxoplasma gondii and Plasmodium falciparum development by selectively targeting a spliceosome kinase

• Published in: Science translational medicine 2022-08, Vol.14 (656), p.eabn3231-eabn3231
• Main Authors: Swale, Christopher, Bellini, Valeria, Bowler, Matthew W., Flore, Nardella, Brenier-Pinchart, Marie-Pierre, Cannella, Dominique, Belmudes, Lucid, Mas, Caroline, Couté, Yohann, Laurent, Fabrice, Scherf, Artur, Bougdour, Alexandre, Hakimi, Mohamed-Ali
• Format: Article
• Language: English
• Subjects: Life Sciences; Santé publique et épidémiologie
• ISSN: 1946-6234; 1946-6242
• DOI: 10.1126/scitranslmed.abn3231

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. Spliceosome targeting by altiratinib leads to Toxoplasma and Plasmodium inhibition. Toxoplasma gondii and Plasmodium falciparum are members of the Apicomplexa phylum of parasitic protists that can cause severe infections in humans and other animals. Available drugs against these parasites have limited efficacy and undesirable side effects. Swale et al. used a drug repurposing screen and identified altiratinib as a potential antiparasitic drug. Altiratinib was originally developed as a drug to treat glioblastoma, and, here, they show that this drug has potent parasiticidal activation against T. gondii . Through drug resistance screening and genetic target deconvolution, Tg PRP4K of T. gondii was identified as the primary target of altiratinib, which was confirmed for its counterpart in P. falciparum , Pf CLK3. Altiratinib was shown to globally