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The 20S proteasome is a validated new drug target against\n                      <jats:italic toggle=\"yes\">T. vaginalis,<\/jats:italic>\n                      but inhibitors of the proteasome complex have so far only shown modest selectivity over human cells. We screened a library of 373 diverse peptide inhibitors with different reactive warheads against diverse\n                      <jats:italic toggle=\"yes\">T. vaginalis<\/jats:italic>\n                      strains in a growth and survival assay and identified several compounds with potencies in the 10\u201320 nM range. Notably, these compounds were up to 200-fold selective for\n                      <jats:italic toggle=\"yes\">T. vaginalis<\/jats:italic>\n                      over mammalian cells and could overcome metronidazole resistance. Removal of the epoxide or the adjacent methyl group in the inhibitors carrying an epoxyketone functionality abolished activity, underlining the functional importance of this warhead. Biochemical and whole-cell assays of inhibitory activity against each of the three catalytically active subunits (\u03b21, \u03b22, and \u03b25) of the proteasome showed that inhibition of \u03b25 was sufficient to mediate activity against\n                      <jats:italic toggle=\"yes\">T. vaginalis<\/jats:italic>\n                      . Furthermore, the high selectivity of the best compounds came from their preferential inhibition of\n                      <jats:italic toggle=\"yes\">T. vaginalis<\/jats:italic>\n                      \u03b25 over human \u03b25. Docking calculations of the most selective inhibitor to the\n                      <jats:italic toggle=\"yes\">T. vaginalis<\/jats:italic>\n                      substrate-binding pocket revealed the formation of two stabilizing hydrogen bonds with a threonine residue that is absent in the human proteasome. These results encourage the therapeutic development of highly potent and selective proteasome inhibitors against\n                      <jats:italic toggle=\"yes\">T. vaginalis<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00893-25","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T19:09:02Z","timestamp":1762888142000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Inhibitors of the 20S proteasome \u03b25 subunit as potent and selective agents against\n                    <i>Trichomonas vaginalis<\/i>"],"prefix":"10.1128","volume":"69","author":[{"given":"Yukiko","family":"Miyamoto","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0168r3w48","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medicine, University of California San Diego","place":["La Jolla, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brianna M.","family":"Hurysz","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0168r3w48","id-type":"ROR","asserted-by":"publisher"}],"name":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego","place":["La Jolla, USA"]},{"id":[{"id":"https:\/\/ror.org\/0168r3w48","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Discovery and Innovation in Parasitic Diseases, University of California San Diego","place":["La Jolla, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavla","family":"Fajtova","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0168r3w48","id-type":"ROR","asserted-by":"publisher"}],"name":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego","place":["La Jolla, USA"]},{"id":[{"id":"https:\/\/ror.org\/0168r3w48","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Discovery and Innovation in Parasitic Diseases, University of California San Diego","place":["La Jolla, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Eckmann","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0168r3w48","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Computer Science and Engineering, University of California San Diego","place":["La Jolla, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mateus S\u00e1 Magalh\u00e3es","family":"Serafim","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0168r3w48","id-type":"ROR","asserted-by":"publisher"}],"name":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego","place":["La Jolla, USA"]},{"id":[{"id":"https:\/\/ror.org\/0168r3w48","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Discovery and Innovation in Parasitic Diseases, University of California San Diego","place":["La Jolla, USA"]},{"id":[{"id":"https:\/\/ror.org\/0176yjw32","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology, Federal University of Minas Gerais (UFMG)","place":["Belo Horizonte, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thales","family":"Kronenberger","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/028s4q594","id-type":"ROR","asserted-by":"publisher"}],"name":"Institut f\u00fcr Medizinische Mikrobiologie und Hygiene, Partner-site T\u00fcbingen, German Center for Infection Research (DZIF)","place":["T\u00fcbingen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Momen","family":"Al-Hindy","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0168r3w48","id-type":"ROR","asserted-by":"publisher"}],"name":"Scripps Institution of Oceanography, University of California San Diego","place":["La Jolla, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick M.","family":"Dekker","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/027bh9e22","id-type":"ROR","asserted-by":"publisher"}],"name":"Gorlaeus Laboratories, Leiden Institute of Chemistry","place":["Leiden, the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elmer","family":"Maurits","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/027bh9e22","id-type":"ROR","asserted-by":"publisher"}],"name":"Gorlaeus Laboratories, Leiden Institute of Chemistry","place":["Leiden, the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herman S.","family":"Overkleeft","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/027bh9e22","id-type":"ROR","asserted-by":"publisher"}],"name":"Gorlaeus Laboratories, Leiden Institute of Chemistry","place":["Leiden, the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. 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