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

  • Nat Commun. 2018 Sep 18;9(1):3805. doi: 10.1038/s41467-018-05777-2.
Michael J Delves  1 ,  Celia Miguel-Blanco  1  2 ,  Holly Matthews  1 ,  Irene Molina  2 ,  Andrea Ruecker  1 ,  Sabrina Yahiya  1 ,  Ursula Straschil  1 ,  Matthew Abraham  3 ,  María Luisa León  2 ,  Oliver J Fischer  4 ,  Ainoa Rueda-Zubiaurre  4 ,  Jochen R Brandt  4 ,  Álvaro Cortés  2 ,  Anna Barnard  4 ,  Matthew J Fuchter  4 ,  Félix Calderón  2 ,  Elizabeth A Winzeler  3 ,  Robert E Sinden  1 ,  Esperanza Herreros  2 ,  Francisco J Gamo  5 ,  Jake Baum  6
Affiliations
  • 1. Department of Life Sciences, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London, SW7 2AZ, UK.
  • 2. Diseases of the Developing World (DDW), GlaxoSmithKline, 28760, Tres Cantos, Madrid, Spain.
  • 3. School of Medicine, University of California San Diego, 9500 Gilman Drive 0760, La Jolla, CA, 92093, USA.
  • 4. Department of Chemistry, Imperial College London, Exhibition Road, South Kensington, London, SW7 2AZ, UK.
  • 5. Diseases of the Developing World (DDW), GlaxoSmithKline, 28760, Tres Cantos, Madrid, Spain. [email protected].
  • 6. Department of Life Sciences, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London, SW7 2AZ, UK. [email protected].
PMID: 30228275 DOI: 10.1038/s41467-018-05777-2
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.

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