Multivariate chemogenomic screening prioritizes new macrofilaricidal leads

Area of Science:

• Drug discovery and development
• Parasitology
• Medicinal chemistry

Background:

• Human filariases are neglected tropical diseases requiring new treatments.
• Current drug screening methods for macrofilaricides are limited by parasite life cycle and low throughput.
• Existing screens often lack enrichment for compounds with true antifilarial potential.

Purpose of the Study:

• To develop a high-throughput, multivariate screening assay for identifying macrofilaricidal compounds.
• To characterize compound activity across multiple parasite fitness parameters.
• To discover novel antifilarial drug leads with improved efficacy and mechanisms of action.

Main Methods:

• Leveraged microfilariae for a primary screening enrichment step.
• Developed multiplexed adult assays assessing neuromuscular control, fecundity, metabolism, and viability.
• Screened a diverse chemogenomic library against both microfilariae and adult parasites.
• Compared microfilariae screening with nematode developmental assays and deep learning-based virtual screening.

Main Results:

• Identified dozens of compounds with submicromolar macrofilaricidal activity, achieving a >50% hit rate.
• Seventeen compounds showed significant effects on adult parasite fitness traits.
• Five compounds demonstrated high adult potency with differential microfilaricidal activity.
• One compound exhibited a novel mechanism of action against adult filarial parasites.

Conclusions:

• Microfilariae-based primary screening significantly outperforms traditional methods for antifilarial drug discovery.
• The developed high-content, multiplexed assays provide a robust platform for identifying novel macrofilaricides.
• This approach offers promising new leads for the development of effective treatments for human filariases.