Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

Laura E de Vries (1) , Patrick a M Jansen (1) , Catalina Barcelo (2) , Justin Munro (3) , Julie M J Verhoef , Charisse Flerida A Pasaje (4) , Kelly Rubiano (5) , Josefine Striepen , Nada Abla , Luuk Berning , Judith M Bolscher , Claudia Demarta-Gatsi (2) , Rob W M Henderson , Tonnie Huijs , Karin M J Koolen , Patrick K Tumwebaze (6) , Tomas Yeo (5) , Anna C C Aguiar (7) , Iñigo Angulo-Barturen (8) , Alisje Churchyard (9) , Jake Baum , Benigno Crespo Fernández (10) , Aline Fuchs , Francisco-Javier Gamo , Rafael V C Guido , María Belén Jiménez-Diaz , Dhelio B Pereira , Rosemary Rochford , Camille Roesch , Laura M Sanz , Graham Trevitt , Benoît Witkowski (11) , Sergio Wittlin , Roland A Cooper , Philip J Rosenthal , Robert W Sauerwein , Joost Schalkwijk , Pedro H H Hermkens , Roger V Bonnert , Brice Campo , David A Fidock , Manuel Llinás , Jacquin C Niles , Taco W A Kooij (1) , Koen J Dechering (12)

1 Radboud University Medical Center [Nijmegen]
2 MMV - Medicines for Malaria Venture [Geneva]
3 Penn State - Pennsylvania State University
4 MIT - Massachusetts Institute of Technology
5 CUIMC - Columbia University Irving Medical Center
6 Infectious Diseases Research Collaboration [Kampala, Ouganda]
7 USP - Universidade de São Paulo = University of São Paulo
8 TAD - The Art of Discovery [Bizkaia, Spain]
9 Imperial College London
10 GlaxoSmithKline
11 MTRU - Malaria Translational Research Unit
12 TropIQ Health Sciences [Nijmegen, The Netherlands]

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.

Domaines: Sciences du Vivant [q-bio]

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⟩