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Inosine monophosphate dehydrogenase (IMPDH) is an essential enzyme in guanine nucleotide salvage pathway and represents a promising alternative target. Here, we combined computational screening, biochemical and cell-based phenotypic assays that support\n                      <jats:italic toggle=\"yes\">T. cruzi<\/jats:italic>\n                      IMPDH (\n                      <jats:italic toggle=\"yes\">Tc<\/jats:italic>\n                      IMPDH) as a druggable target and identify repurposing opportunities among clinical-stage inhibitors. Using Tanimoto similarity scoring against the library of 222 Chagas Box compounds, we identified TCMDC-143376 as uniquely similar to the clinical IMPDH inhibitors merimepodib and AVN-944. Phylogenetic analysis and multiple sequence alignment confirmed conservation of both catalytic and allosteric residues\u2014drawn from\n                      <jats:italic toggle=\"yes\">T. foetus<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">T. brucei<\/jats:italic>\n                      structures\u2014within\n                      <jats:italic toggle=\"yes\">Tc<\/jats:italic>\n                      IMPDH. Recombinant\n                      <jats:italic toggle=\"yes\">Tc<\/jats:italic>\n                      IMPDH kinetics revealed Michaelis constants of 155 \u00b5M for IMP and 292 \u00b5M for NAD\n                      <jats:sup>+<\/jats:sup>\n                      . Biochemical IC\n                      <jats:sub>50<\/jats:sub>\n                      assays showed submicromolar inhibition by AVN-944 (0.20 \u00b5M), (S)-Merimepodib (0.21 \u00b5M), and (R)-Merimepodib (0.37 \u00b5M). In H9c2 cardiomyoblasts infected with intracellular amastigotes, AVN-944 achieved the lowest EC\n                      <jats:sub>50<\/jats:sub>\n                      (0.4 \u00b5M), outperforming benznidazole (EC\n                      <jats:sub>50<\/jats:sub>\n                      = 3.0 \u00b5M) and other inhibitors. Our findings support\n                      <jats:italic toggle=\"yes\">Tc<\/jats:italic>\n                      IMPDH as a promising alternative drug target for Chagas disease and position AVN-944 as a compelling candidate to evaluate this therapeutic strategy in animal models.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.01210-25","type":"journal-article","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T14:00:26Z","timestamp":1769090426000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Exploring\n                    <i>T. cruzi<\/i>\n                    IMPDH as a promising target through Chagas Box screening and AVN-944 inhibition"],"prefix":"10.1128","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1624-8292","authenticated-orcid":true,"given":"Angel","family":"Lobo-Rojas","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04kjcjc51","id-type":"ROR","asserted-by":"publisher"}],"name":"Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials","place":["Campinas, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1955-9184","authenticated-orcid":true,"given":"Let\u00edcia","family":"Marchese","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04kjcjc51","id-type":"ROR","asserted-by":"publisher"}],"name":"Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials","place":["Campinas, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7253-9908","authenticated-orcid":true,"given":"Amanda G.","family":"Eufrasio","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04kjcjc51","id-type":"ROR","asserted-by":"publisher"}],"name":"Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials","place":["Campinas, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3923-5678","authenticated-orcid":true,"given":"Gabriel T. 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