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