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

Area of Science:

• Drug Discovery and Development
• Parasitology
• Medicinal Chemistry

Background:

• Parasitic helminth infections cause significant health burdens in humans and animals.
• Increasing anthelmintic resistance necessitates the development of novel drugs.
• Early-stage drug discovery faces challenges including limited starting points, model predictivity, and mechanistic understanding.

Purpose of the Study:

• To present an iterative framework for early-stage anthelmintic drug discovery.
• To integrate complementary discovery routes and medicinal chemistry efforts.
• To guide experimental decisions through mechanism-informed approaches.

Main Methods:

• Utilizing target-agnostic whole-organism screening and target-based approaches.
• Employing chemoproteomics, functional genomics, and multi-omics for target identification.
• Leveraging artificial intelligence for compound and hypothesis prioritization.
• Integrating structure-activity relationship analysis and translational assessment.

Main Results:

• A framework connecting diverse screening routes with hit confirmation, mechanistic investigation, and translational assessment is proposed.
• Nematode models offer scalable platforms, with trematode and cestode examples showing broader applicability.
• While measurable activity can be identified, development-quality hit series remain infrequent.

Conclusions:

• An integrated, experimentally grounded, and mechanism-informed approach is essential for early-stage anthelmintic discovery.
• Success requires not only scientific integration but also sustained investment, cross-sector expertise, and development infrastructure.
• The proposed framework aims to address current limitations and accelerate the identification of new anthelmintic therapies.