A high throughput screen for next-generation leads targeting malaria parasite transmission View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-12

AUTHORS

Michael J. Delves, Celia Miguel-Blanco, Holly Matthews, Irene Molina, Andrea Ruecker, Sabrina Yahiya, Ursula Straschil, Matthew Abraham, María Luisa León, Oliver J. Fischer, Ainoa Rueda-Zubiaurre, Jochen R. Brandt, Álvaro Cortés, Anna Barnard, Matthew J. Fuchter, Félix Calderón, Elizabeth A. Winzeler, Robert E. Sinden, Esperanza Herreros, Francisco J. Gamo, Jake Baum

ABSTRACT

Spread of parasite resistance to artemisinin threatens current frontline antimalarial therapies, highlighting the need for new drugs with alternative modes of action. Since only 0.2-1% of asexual parasites differentiate into sexual, transmission-competent forms, targeting this natural bottleneck provides a tangible route to interrupt disease transmission and mitigate resistance selection. Here we present a high-throughput screen of gametogenesis against a ~70,000 compound diversity library, identifying seventeen drug-like molecules that target transmission. Hit molecules possess varied activity profiles including male-specific, dual acting male-female and dual-asexual-sexual, with one promising N-((4-hydroxychroman-4-yl)methyl)-sulphonamide scaffold found to have sub-micromolar activity in vitro and in vivo efficacy. Development of leads with modes of action focussed on the sexual stages of malaria parasite development provide a previously unexplored base from which future therapeutics can be developed, capable of preventing parasite transmission through the population. More... »

PAGES

3805

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41467-018-05777-2

    DOI

    http://dx.doi.org/10.1038/s41467-018-05777-2

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1106952165

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30228275


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