Multivariate chemogenomic screening prioritizes new macrofilaricidal leads.

Autor: Wheeler NJ; Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, WI, USA.; Department of Biology, University of Wisconsin-Eau Claire, Eau Claire, WI, USA., Ryan KT; Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, WI, USA., Gallo KJ; Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, WI, USA., Henthorn CR; Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, WI, USA., Ericksen SS; Small Molecule Screening Facility, Drug Development Core, UW-Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA., Chan JD; Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, WI, USA.; Department of Chemistry, University of Wisconsin-Oshkosh, Oshkosh, WI, USA., Zamanian M; Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, WI, USA. mzamanian@wisc.edu.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2023 Jan 13; Vol. 6 (1), pp. 44. Date of Electronic Publication: 2023 Jan 13.
DOI: 10.1038/s42003-023-04435-8
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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