An Onto-Epistemic Framework for Systematic Discovery of Druggable Protein and Cell-Surface Receptors in Trypanosoma cruzi

The persistent therapeutic gap in Chagas disease stems largely from an incomplete understanding of which Trypanosoma cruzi components are both indispensable to parasite fitness and experimentally tractable. We propose a two-tiered strategy that first defines vulnerability in ontological termsparasite-essentiality, host-selectivity, stage expression profile, and structural addressability-and then validates each candidate through a progressively stringent epistemological pipeline. Starting with genome-wide annotations and stage-resolved transcriptomes, flux-balance modelling and CRISPR fitness screens winnow the proteome to a core set of essential, human-absent proteins. Structure prediction with AlphaFold2, pocket scoring, and epitope mapping next rank targets by druggability or immunogenic potential. Multi-criteria decision analysis integrates these metrics to prioritise the top ten receptors for experimental interrogation. Conditional knockouts , phenotypic rescue, small-molecule docking, antibody neutralisation assays, and in-vivo murine models constitute successive decision gates, each designed to falsify weak hypotheses early and conserve resources. This onto-epistemic framework not only accelerates identification of high-confidence targets such as TcP21, TcAkt, and GP63 metalloproteases but also provides a reproducible blueprint adaptable to other kinetoplastids. By unifying conceptual clarity with methodological rigour, the workflow maximises the probability that a validated receptor will translate into clinically viable therapies for Chagas disease.