Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183 - Institut Pasteur Access content directly
Journal Articles Nature Communications Year : 2022

Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

Julie M J Verhoef
  • Function : Author
Josefine Striepen
  • Function : Author
Nada Abla
  • Function : Author
Luuk Berning
  • Function : Author
Judith M Bolscher
  • Function : Author
Rob W M Henderson
  • Function : Author
Tonnie Huijs
  • Function : Author
Karin M J Koolen
  • Function : Author
Jake Baum
Aline Fuchs
  • Function : Author
Francisco-Javier Gamo
  • Function : Author
Rafael V C Guido
  • Function : Author
María Belén Jiménez-Diaz
  • Function : Author
Dhelio B Pereira
  • Function : Author
Rosemary Rochford
  • Function : Author
Camille Roesch
Laura M Sanz
  • Function : Author
Graham Trevitt
  • Function : Author
Benoît Witkowski
  • Function : Author
  • PersonId : 751218
  • IdHAL : bwitkowski
Sergio Wittlin
  • Function : Author
Roland A Cooper
  • Function : Author
Philip J Rosenthal
  • Function : Author
Robert W Sauerwein
  • Function : Author
Joost Schalkwijk
  • Function : Author
Pedro H H Hermkens
  • Function : Author
Roger V Bonnert
  • Function : Author
Brice Campo
  • Function : Author
David A Fidock
  • Function : Author
Manuel Llinás
  • Function : Author
Jacquin C Niles
  • Function : Author

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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pasteur-03699217 , version 1 (20-06-2022)

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Laura E de Vries, Patrick a M Jansen, Catalina Barcelo, Justin Munro, Julie M J Verhoef, et al.. Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183. Nature Communications, 2022, 13 (1), pp.2158. ⟨10.1038/s41467-022-29688-5⟩. ⟨pasteur-03699217⟩
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