Early-stage anthelmintic discovery: Integrating phenotype, target and mechanism

Parasitic helminth infections impose major burdens on human and animal health, and increasing anthelmintic resistance reinforces the need for new drugs. Early-stage discovery remains constrained by the scarcity of novel, potent, selective and chemically tractable starting points, the limited predictive value of some experimental models, mechanistic uncertainty and insufficient capacity to sustain promising series through medicinal chemistry, safety and exposure studies. Discovery can begin through complementary routes, including target-agnostic whole-organism screening, screening of known-pharmacology and repurposing collections, target- or pathway-led approaches and structure-guided or computational selection. Whole-organism models are valuable because they capture compound access and integrated parasite responses, but do not establish mechanism; conversely, target-based approaches require validation in the intact parasite. This review presents an iterative framework connecting these entry routes with chemical diversity, hit confirmation and triage, early structure-activity relationship analysis, fit-for-purpose mechanistic investigation and translational assessment. Nematode models provide scalable platforms, while selected trematode and cestode examples illustrate broader applicability. Chemoproteomics, functional genomics and multi-omics can link phenotypes to candidate targets and pathways, while artificial intelligence can support compound and hypothesis prioritisation. Their value lies in informing experimental decisions rather than replacing validation. Quantitative examples show that measurable activity can be identified, but development-quality hit series remain rare. Scientific integration is therefore necessary but insufficient: sustained investment, cross-sector expertise, development infrastructure and continuity of project ownership are also required. Together, these principles define a balanced, experimentally grounded and mechanism-informed approach to early-stage anthelmintic discovery.