Cruzain Inhibitors for Chagas Disease: Anticorrelated Optimisation Landscapes and the Multiparametric Path to...

Over three decades, cruzain, the principal cysteine protease of Trypanosoma cruzi and a validated drug target for Chagas disease, has accumulated 215 inhibitors with IC₅₀ ≤ 1 μM, more than 30 crystal structures, and no clinical candidates. 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-peptidic 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-energy perturbation and machine-learning QSAR) have been applied with increasing sophistication, but against affinity-centred objectives that underrepresent exposure constraints. As its principal contribution, this work proposes a multiparametric optimisation framework, provisional viability benchmarks, and a feasibility-envelope concept that reframes cruzain inhibitor discovery as a constraint-satisfaction rather than a potency-maximisation problem. The framework outlines provisional quantitative criteria that a next-generation cruzain lead would likely need to satisfy and explains why structurally tractable intracellular cysteine protease targets can remain clinically unrealised.