4.7 Article

Multivariate chemogenomic screening prioritizes new macrofilaricidal leads

Journal

COMMUNICATIONS BIOLOGY
Volume 6, Issue 1, Pages -

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s42003-023-04435-8

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The development of direct acting macrofilaricides for the treatment of human filariases faces limitations in screening throughput due to the parasite life cycle. A multivariate screen using microfilariae identified dozens of compounds with submicromolar macrofilaricidal activity, achieving a hit rate of over 50%. Thorough characterization of compound activity on adult traits led to the discovery of five compounds with high potency against adults, but low potency or slow-acting microfilaricidal effects.
Development of direct acting macrofilaricides for the treatment of human filariases is hampered by limitations in screening throughput imposed by the parasite life cycle. In vitro adult screens typically assess single phenotypes without prior enrichment for chemicals with antifilarial potential. We developed a multivariate screen that identified dozens of compounds with submicromolar macrofilaricidal activity, achieving a hit rate of >50% by leveraging abundantly accessible microfilariae. Adult assays were multiplexed to thoroughly characterize compound activity across relevant parasite fitness traits, including neuromuscular control, fecundity, metabolism, and viability. Seventeen compounds from a diverse chemogenomic library elicited strong effects on at least one adult trait, with differential potency against microfilariae and adults. Our screen identified five compounds with high potency against adults but low potency or slow-acting microfilaricidal effects, at least one of which acts through a novel mechanism. We show that the use of microfilariae in a primary screen outperforms model nematode developmental assays and virtual screening of protein structures inferred with deep learning. These data provide new leads for drug development, and the high-content and multiplex assays set a new foundation for antifilarial discovery. A comprehensive optimization of phenotypic and computational screening strategy for antifilarial drug and target discovery identifies compounds with stage, species, and/or sex-specific activity, some with submicromolar potency.

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