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Classical inhibitors acting at the active site have shown limited success due to poor selectivity, suboptimal pharmacological properties, and lack of in\u2010cell efficacy. This work presents a comprehensive strategy to develop first\u2010in\u2010class Li\u2010TryR dimerization disruptors, targeting the protein\u2013protein interface required for enzymatic activity. Through molecular modeling, mutagenesis, and structural analysis, a key \u03b1\u2010helical hotspot (around residue E436) was identified as a druggable region. Interface\u2010derived peptides, helix\u2010stabilized stapled analogs, \u03b1\/\u03b2\u2010foldamers, and cell\u2010penetrating conjugates demonstrated that dimer disruption effectively inhibits LiTryR and can translate into antiparasitic activity. Building on these insights, several families of small\u2010molecule proteomimetics, including imidazole\u2010phenyl\u2010thiazoles, triazole analogs, and triazolium salts, were developed, achieving low\u2010micromolar to submicromolar inhibition and significant activity in parasite cultures and intracellular models. Overall, this work establishes dimer\u2010interface targeting as a novel therapeutic paradigm for leishmaniasis and provides multiple optimized chemical scaffolds for future drug development.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70513","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T03:20:27Z","timestamp":1790565627000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond the Active Site: First\u2010In\u2010Class Leishmania Infantum Trypanothione Reductase Dimerization Disruptors as Antileishmanial Leads"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4978-6468","authenticated-orcid":false,"given":"Mar\u00eda\u2010Jos\u00e9","family":"Camarasa","sequence":"first","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica y Biomedicina (IQMB\u2010CSIC)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2166-7088","authenticated-orcid":false,"given":"Miguel","family":"Maldonado","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica y Biomedicina (IQMB\u2010CSIC)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9891-8996","authenticated-orcid":false,"given":"Alvaro","family":"de la Cruz\u2010Potenciano","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica y Biomedicina (IQMB\u2010CSIC)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3838-6856","authenticated-orcid":false,"given":"Sonia","family":"de Castro","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica y Biomedicina (IQMB\u2010CSIC)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,27]]},"reference":[{"key":"e_1_2_9_2_1","first-page":"366","article-title":"Evaluation of Susceptibility Status of Phlebotomus Papatasi, the Main Vector of Zoonotic Cutaneous Leishmaniasis, to Different WHO Recommended Insecticides in an Endemic Focus, Central Iran","volume":"15","author":"Saeidi Z.","year":"2021","journal-title":"Journal of Arthropod\u2010Borne Diseases"},{"key":"e_1_2_9_3_1","first-page":"217e231","article-title":"Anti\u2010Trypanosomatid Drug Discovery: An Ongoing Challenge and a Continuing Need","volume":"15","author":"Field M. 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