Poster Presentation First Malaria World Congress 2018

A high throughput screen for next-generation leads targeting malaria parasite transmission (#236)

Michael Delves 1 , Celia Miguel-Blanco 2 , Holly Matthews 1 , Irene Molina 2 , Andrea Ruecker 1 , Sabrina Yahiya 1 , Ursula Straschil 1 , Matthew Abraham 3 , Maria-Luisa Leon 2 , Oliver Fischer 1 , Ainoa Zubiaurre 1 , Jochen Brandt 1 , Alvaro Cortes 2 , Anna Barnard 1 , Matthew Fuchter 1 , Felix Calderon 2 , Elizabeth Winzeler 3 , Bob Sinden 1 , Esperanza Herreros 2 , Francisco J Gamo 2 , Jake Baum 1
  1. Imperial College London, South Kensington, London, UK, United Kingdom
  2. GlaxoSmithKline, Tres Cantos, Madrid, Spain
  3. School of Medicine, University of California San Diego, La Jolla, CA, USA

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 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.