Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

Laura E. Vries, Patrick A. M. Jansen, Catalina Barcelo, Justin Munro, Julie M. J. Verhoef, Charisse Flerida A. Pasaje, Kelly Rubiano, Josefine Striepen, Nada Abla, Luuk Berning, Judith M. Bolscher, Claudia Demarta-Gatsi, Rob W. M. Henderson, Tonnie Huijs, Karin M. J. Koolen, Patrick K. Tumwebaze, Tomas Yeo, Anna C. C. Aguiar, Iñigo Angulo-Barturen, Alisje Churchyard, Jake Baum, Benigno Crespo Fernández, 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, Benoit Witkowski, 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 () and Koen J. Dechering ()
Additional contact information
Laura E. Vries: Radboud Institute for Molecular Life Sciences, Radboud University Medical Center
Patrick A. M. Jansen: Radboud Institute for Molecular Life Sciences, Radboud University Medical Center
Catalina Barcelo: Medicines for Malaria Venture
Justin Munro: The Pennsylvania State University
Julie M. J. Verhoef: Radboud Institute for Molecular Life Sciences, Radboud University Medical Center
Charisse Flerida A. Pasaje: Massachusetts Institute of Technology
Kelly Rubiano: Columbia University Irving Medical Center
Josefine Striepen: Columbia University Irving Medical Center
Nada Abla: Medicines for Malaria Venture
Luuk Berning: TropIQ Health Sciences
Judith M. Bolscher: TropIQ Health Sciences
Claudia Demarta-Gatsi: Medicines for Malaria Venture
Rob W. M. Henderson: TropIQ Health Sciences
Tonnie Huijs: TropIQ Health Sciences
Karin M. J. Koolen: TropIQ Health Sciences
Patrick K. Tumwebaze: Infectious Diseases Research Collaboration
Tomas Yeo: Columbia University Irving Medical Center
Anna C. C. Aguiar: Sao Carlos Institute of Physics, University of São Paulo, São Carlos, São Paulo, Brazil
Iñigo Angulo-Barturen: The Art of Discovery
Alisje Churchyard: Imperial College London
Jake Baum: Imperial College London
Benigno Crespo Fernández: Global Health, GlaxoSmithKline
Aline Fuchs: Medicines for Malaria Venture
Francisco-Javier Gamo: Global Health, GlaxoSmithKline
Rafael V. C. Guido: Sao Carlos Institute of Physics, University of São Paulo, São Carlos, São Paulo, Brazil
María Belén Jiménez-Diaz: The Art of Discovery
Dhelio B. Pereira: Research Center for Tropical Medicine of Rondonia
Rosemary Rochford: University of Colorado Anschutz School of Medicine
Camille Roesch: Institut Pasteur du Cambodge
Laura M. Sanz: Global Health, GlaxoSmithKline
Graham Trevitt: Sygnature Discovery
Benoit Witkowski: Institut Pasteur du Cambodge
Sergio Wittlin: Swiss Tropical and Public Health Institute
Roland A. Cooper: Dominican University of California
Philip J. Rosenthal: University of California
Robert W. Sauerwein: Radboud Institute for Molecular Life Sciences, Radboud University Medical Center
Joost Schalkwijk: Radboud Institute for Molecular Life Sciences, Radboud University Medical Center
Pedro H. H. Hermkens: Hermkens Pharma Consultancy
Roger V. Bonnert: Medicines for Malaria Venture
Brice Campo: Medicines for Malaria Venture
David A. Fidock: Columbia University Irving Medical Center
Manuel Llinás: The Pennsylvania State University
Jacquin C. Niles: Massachusetts Institute of Technology
Taco W. A. Kooij: Radboud Institute for Molecular Life Sciences, Radboud University Medical Center
Koen J. Dechering: TropIQ Health Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29688-5

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