| Summary: | <jats:title>Abstract</jats:title><jats:p>Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of <jats:italic>Plasmodium falciparum</jats:italic> infection. The compound shows single digit nanomolar in vitro activity against <jats:italic>P. falciparum</jats:italic> and <jats:italic>P. vivax</jats:italic> clinical isolates, and potently blocks <jats:italic>P. falciparum</jats:italic> transmission to <jats:italic>Anopheles</jats:italic> mosquitoes. Genetic and biochemical studies identify AcAS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. Pharmacokinetic-pharmacodynamic modelling predict that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. Toxicology studies in rats indicate a > 30-fold safety margin in relation to the predicted human efficacious exposure. In conclusion, MMV693183 represents a promising candidate for further (pre)clinical development with a novel mode of action for treatment of malaria and blocking transmission.</jats:p>
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