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

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

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.

• Journal Article Type: Article
• Online Publication Date: Sep 18, 2018
• Publication Date: Sep 18, 2018
• Deposit Date: May 23, 2025
• Publicly Available Date: May 23, 2025
• Journal: Nature Communications
• Print ISSN: 2041-1723
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Article Number: 3805
• DOI: https://doi.org/10.1038/s41467-018-05777-2