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This review argues that the resulting translational paradox reflects not target invalidity, but a persistent strategic mismatch between how cruzain inhibitors have been optimised and what intracellular efficacy requires. Across peptidyl vinyl sulfones, non\u2010peptidic scaffolds, and thiosemicarbazones, enzymatic potency has been systematically prioritised over the coupled determinants of intracellular exposure: permeability, metabolic stability, and cathepsin selectivity. Each inhibitor class fails for a distinct proximal reason, and these failures converge on the same optimisation bias. Computational approaches (docking, molecular dynamics, free\u2010energy perturbation and machine\u2010learning QSAR) have been applied with increasing sophistication, but against affinity\u2010centred objectives that underrepresent exposure constraints. As its principal contribution, this work proposes a multiparametric optimisation framework, provisional viability benchmarks, and a feasibility\u2010envelope concept that reframes cruzain inhibitor discovery as a constraint\u2010satisfaction rather than a potency\u2010maximisation problem. The framework outlines provisional quantitative criteria that a next\u2010generation cruzain lead would likely need to satisfy and explains why structurally tractable intracellular cysteine protease targets can remain clinically unrealised.\n                  <\/jats:p>","DOI":"10.1111\/cbdd.70340","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T06:00:35Z","timestamp":1781503235000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cruzain Inhibitors for Chagas Disease: Anticorrelated Optimisation Landscapes and the Multiparametric Path to Clinical Candidates"],"prefix":"10.1111","volume":"107","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8982-242X","authenticated-orcid":false,"given":"Caroline Rodrigues Chaves","family":"dos Reis","sequence":"first","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz, Fiocruz, Instituto de Tecnologia em F\u00e1rmacos, Programa de 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