Structural and functional characterization of TgGSK3, a druggable kinase in Toxoplasma gondii

Silvia Diaz-Martin, Christopher Swale, Valeria Bellini, Irina Dobrescu, Janine Wenker, Marie-Pierre Brenier-Pinchart, Laurence Braun, Alwéna Tollec, Charlotte Corrao, Yohann Couté, Caroline Mas, Fabrice Laurent, Matthew Bowler, Mohamed-Ali Hakimi () and Alexandre Bougdour ()
Additional contact information
Silvia Diaz-Martin: University Grenoble Alpes
Christopher Swale: University Grenoble Alpes
Valeria Bellini: University Grenoble Alpes
Irina Dobrescu: Laboratoire Apicomplexes et Immunité Mucosale
Janine Wenker: Laboratoire Apicomplexes et Immunité Mucosale
Marie-Pierre Brenier-Pinchart: University Grenoble Alpes
Laurence Braun: University Grenoble Alpes
Alwéna Tollec: CEA
Charlotte Corrao: University Grenoble Alpes
Yohann Couté: CEA
Caroline Mas: EMBL
Fabrice Laurent: Laboratoire Apicomplexes et Immunité Mucosale
Matthew Bowler: CS 90181
Mohamed-Ali Hakimi: University Grenoble Alpes
Alexandre Bougdour: University Grenoble Alpes

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Toxoplasma gondii and Cryptosporidium species are apicomplexan parasites of significant medical and veterinary importance. Although current therapeutic options for toxoplasmosis and cryptosporidiosis demonstrate notable efficacy, their clinical efficacy is often limited by suboptimal efficacy and frequent adverse effects. Moreover, therapeutic alternatives remain limited or nonexistent, particularly for cryptosporidiosis, for which nitazoxanide is currently the only approved medication to treat diarrhea in adults and children older than 1 year of age. To identify alternative therapeutic options for addressing these health challenges, we performed a phenotypic screening of an FDA-approved drug repurposing library against Toxoplasma. This screening identifies LY2090314 as a potent inhibitor of T. gondii and Cryptosporidium growth in mammalian cells. Through a target deconvolution strategy combining forward genetics, transcriptome sequencing, and computational mutation analysis, we elucidate the parasiticidal mechanism of LY2090314 and demonstrate that TgGSK3 kinase is its primary molecular target. We also report the first X-ray crystal structure of LY2090314 bound to TgGSK3, resolved at 2.1 Å, which reveals an interaction mode characteristic of type I ATP-competitive inhibitors. Furthermore, interactome analysis uncovers functional connections between TgGSK3 and key cytoskeletal and signaling regulators, providing insights into compound’s effects. Collectively, these findings validate TgGSK3 as a promising therapeutic target for toxoplasmosis and offer mechanistic insights into apicomplexan GSK3 biology.

Date: 2025
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DOI: 10.1038/s41467-025-64701-7

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