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

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 () and Jake Baum ()
Additional contact information
Michael J. Delves: Imperial College London, Sir Alexander Fleming Building
Celia Miguel-Blanco: Imperial College London, Sir Alexander Fleming Building
Holly Matthews: Imperial College London, Sir Alexander Fleming Building
Irene Molina: Diseases of the Developing World (DDW), GlaxoSmithKline
Andrea Ruecker: Imperial College London, Sir Alexander Fleming Building
Sabrina Yahiya: Imperial College London, Sir Alexander Fleming Building
Ursula Straschil: Imperial College London, Sir Alexander Fleming Building
Matthew Abraham: University of California San Diego
María Luisa León: Diseases of the Developing World (DDW), GlaxoSmithKline
Oliver J. Fischer: Imperial College London
Ainoa Rueda-Zubiaurre: Imperial College London
Jochen R. Brandt: Imperial College London
Álvaro Cortés: Diseases of the Developing World (DDW), GlaxoSmithKline
Anna Barnard: Imperial College London
Matthew J. Fuchter: Imperial College London
Félix Calderón: Diseases of the Developing World (DDW), GlaxoSmithKline
Elizabeth A. Winzeler: University of California San Diego
Robert E. Sinden: Imperial College London, Sir Alexander Fleming Building
Esperanza Herreros: Diseases of the Developing World (DDW), GlaxoSmithKline
Francisco J. Gamo: Diseases of the Developing World (DDW), GlaxoSmithKline
Jake Baum: Imperial College London, Sir Alexander Fleming Building

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05777-2

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DOI: 10.1038/s41467-018-05777-2

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