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Current therapies are limited by toxicity, poor efficacy against chronic infection, and lack of activity against tissue cysts, highlighting the need for new therapeutic strategies. Aspartic proteases represent promising but underexplored drug targets in\n                      <jats:italic toggle=\"yes\">T. gondii<\/jats:italic>\n                      . In this study, we evaluated the anti-\n                      <jats:italic toggle=\"yes\">T<\/jats:italic>\n                      .\n                      <jats:italic toggle=\"yes\">gondii<\/jats:italic>\n                      potential of a panel of aspartic protease inhibitors initially developed for inhibition of\n                      <jats:italic toggle=\"yes\">Plasmodium<\/jats:italic>\n                      . Eleven compounds were screened\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      against intracellular tachyzoites (RH strain) in human foreskin fibroblasts (HFF), and their cytotoxicity was assessed to determine EC\n                      <jats:sub>50<\/jats:sub>\n                      , CC\n                      <jats:sub>50<\/jats:sub>\n                      , and selectivity indices. Most compounds displayed micromolar activity (EC\n                      <jats:sub>50<\/jats:sub>\n                      range: 1.06\u201375.86 \u00b5M), with CWHM-032 (=TCMDC-134675), CWHM-033 (=TCMDC-136879), and CWHM-117 emerging as the most potent inhibitors. Based on its\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      selective activity, predicted pharmacokinetic and safety profile, and previously reported efficacy against experimental malaria, CWHM-117 was selected for\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      evaluation. In an acute murine model of toxoplasmosis, treatment with CWHM-117 delayed mortality compared to the vehicle-treated group. In a chronic infection model, CWHM-117 significantly reduced cerebral cyst burden (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt; 0.05), demonstrating activity against the bradyzoite stage, which remains a major therapeutic challenge. Overall, these findings indicate that aspartic protease inhibitors, particularly CWHM-117, represent promising lead compounds for the treatment of toxoplasmosis. This study supports\n                      <jats:italic toggle=\"yes\">T. gondii<\/jats:italic>\n                      aspartic proteases as druggable targets and encourages further optimization and mechanistic studies to advance this class of compounds toward preclinical development.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00370-26","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T12:00:44Z","timestamp":1782129644000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["<i>In vitro<\/i>\n                    and\n                    <i>in vivo<\/i>\n                    activity of the aspartic protease inhibitor CWHM-117 against\n                    <i>Toxoplasma gondii<\/i>"],"prefix":"10.1128","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3706-9099","authenticated-orcid":false,"given":"Gabriela P. dos","family":"Santos","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03ywskk07","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Preclinical Assays and Research of Alternative Sources of Innovative Therapy for Toxoplasmosis and Other Sicknesses (PARASITTOS), Faculdade de Medicina de Jundia\u00edi","place":["Jundia\u00ed, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6526-0749","authenticated-orcid":true,"given":"Ingrid de O.","family":"Dias","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03ywskk07","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Preclinical Assays and Research of Alternative Sources of Innovative Therapy for Toxoplasmosis and Other Sicknesses (PARASITTOS), Faculdade de Medicina de Jundia\u00edi","place":["Jundia\u00ed, 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