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Consequently, identifying new drugs by exploring novel protein targets is essential for effective intervention. Cyclosporin A (CsA) possesses antiparasitic activity against <jats:italic>Toxoplasma gondii<\/jats:italic>, with cyclophilins identified as possible targets. However, CsA immunosuppressive nature hinders its use as an antitoxoplasmosis agent. Here, we evaluate the potential of three CsA derivatives devoid of immunosuppressive activity, namely, NIM811, Alisporivir, and dihydrocyclosporin A to target a previously characterized cyclophilin from <jats:italic>Toxoplasma gondii<\/jats:italic> (TgCyp23). We determined the X\u2010ray crystal structures of TgCyp23 in complex with the three analogs and elucidated their binding and inhibitory properties. The high resolution of the structures revealed the precise positioning of ligands within the TgCyp23 binding site and the details of protein\u2013ligand interactions. A comparison with the established ternary structure involving calcineurin indicates that substitutions at position 4 in CsA derivatives prevent calcineurin binding. This finding provides a molecular explanation for why CsA analogs can target Toxoplasma cyclophilins without compromising the human immune response.<\/jats:p>","DOI":"10.1002\/pro.5157","type":"journal-article","created":{"date-parts":[[2024,9,23]],"date-time":"2024-09-23T15:43:49Z","timestamp":1727106229000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Evaluating the potential of non\u2010immunosuppressive cyclosporin analogs for targeting <i>Toxoplasma gondii<\/i> cyclophilin: Insights from structural studies"],"prefix":"10.1002","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2964-1157","authenticated-orcid":false,"given":"Filippo","family":"Favretto","sequence":"first","affiliation":[{"name":"Department of Biotechnology University of Verona  Verona 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