Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

20 Apr 2022

de Vries LE, Jansen PAM, Barcelo C, Munro J, Verhoef JMJ, Pasaje CFA, Rubiano K, Striepen J, Abla N, Berning L, Bolscher JM, Demarta-Gatsi C, Henderson RWM, Huijs T, Koolen KMJ, Tumwebaze PK, Yeo T, Aguiar ACC, Angulo-Barturen I, Churchyard A, Baum J, Fernández BC, Fuchs A, Gamo FJ, Guido RVC, Jiménez-Diaz MB, Pereira DB, Rochford R, Roesch C, Sanz LM, Trevitt G, Witkowski B, Wittlin S, Cooper RA, Rosenthal PJ, Sauerwein RW, Schalkwijk J, Hermkens PHH, Bonnert RV, Campo B, Fidock DA, Llinás M, Niles JC, Kooij TWA, Dechering KJ

Nature Communications
PMID: 35444200

Doi: 10.1038/s41467-022-29688-5

Photo: Jackson_iStock

ABSTRACT

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 Plasmodium falciparum infection. The compound shows single digit nanomolar in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocks P. falciparum transmission to Anopheles 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.

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