2. Academic Validation
  3. Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

  • Nat Commun. 2022 Apr 20;13(1):2158. doi: 10.1038/s41467-022-29688-5.
Laura E de Vries 1 2,  Patrick A M Jansen 3,  Catalina Barcelo 4,  Justin Munro 5,  Julie M J Verhoef 1,  Charisse Flerida A Pasaje 6,  Kelly Rubiano 7,  Josefine Striepen 7,  Nada Abla 4,  Luuk Berning 8,  Judith M Bolscher 8,  Claudia Demarta-Gatsi 4,  Rob W M Henderson 8,  Tonnie Huijs 8,  Karin M J Koolen 8,  Patrick K Tumwebaze 9,  Tomas Yeo 7,  Anna C C Aguiar 10,  Iñigo Angulo-Barturen 11,  Alisje Churchyard 12,  Jake Baum 12,  Benigno Crespo Fernández 13,  Aline Fuchs 4,  Francisco-Javier Gamo 13,  Rafael V C Guido 10,  María Belén Jiménez-Diaz 11,  Dhelio B Pereira 14,  Rosemary Rochford 15,  Camille Roesch 16 17,  Laura M Sanz 13,  Graham Trevitt 18,  Benoit Witkowski 16 17,  Sergio Wittlin 19 20,  Roland A Cooper 21,  Philip J Rosenthal 22,  Robert W Sauerwein 1 8,  Joost Schalkwijk 3,  Pedro H H Hermkens 23,  Roger V Bonnert 4,  Brice Campo 4,  David A Fidock 7 24,  Manuel Llinás 5 25,  Jacquin C Niles 6,  Taco W A Kooij # 26,  Koen J Dechering # 27
Affiliations

Affiliations

  • 1 Department of Medical Microbiology, Radboudumc Center for Infectious Diseases, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
  • 2 Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • 3 Department of Dermatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
  • 4 Medicines for Malaria Venture, Geneva, Switzerland.
  • 5 Department of Chemistry and Huck Center for Malaria Research, The Pennsylvania State University, University Park, PA, USA.
  • 6 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 7 Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY, USA.
  • 8 TropIQ Health Sciences, Nijmegen, The Netherlands.
  • 9 Infectious Diseases Research Collaboration, Kampala, Uganda.
  • 10 Sao Carlos Institute of Physics, University of São Paulo, São Carlos, São Paulo, Brazil, São Carlos, SP, Brazil.
  • 11 The Art of Discovery, Derio, Spain.
  • 12 Department of Life Sciences, Imperial College London, South Kensington, London, United Kingdom.
  • 13 Global Health, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
  • 14 Research Center for Tropical Medicine of Rondonia, Porto Velho, Brazil.
  • 15 Department of Immunology and Microbiology, University of Colorado Anschutz School of Medicine, Aurora, CO, USA.
  • 16 Malaria Molecular Epidemiology Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia.
  • 17 Malaria Translational Research Unit, Institut Pasteur, Paris & Institut Pasteur du Cambodge, Phnom Penh, Cambodia.
  • 18 Sygnature Discovery, Nottingham, United Kingdom.
  • 19 Swiss Tropical and Public Health Institute, Basel, Switzerland.
  • 20 University of Basel, Basel, Switzerland.
  • 21 Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, CA, USA.
  • 22 Department of Medicine, University of California, San Francisco, CA, USA.
  • 23 Hermkens Pharma Consultancy, Oss, The Netherlands.
  • 24 Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
  • 25 Department of Biochemistry & Molecular Biology, The Pennsylvania State University, University Park, PA, USA.
  • 26 Department of Medical Microbiology, Radboudumc Center for Infectious Diseases, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. taco.kooij@radboudumc.nl.
  • 27 TropIQ Health Sciences, Nijmegen, The Netherlands. k.dechering@tropiq.nl.
  • # Contributed equally.
PMID: 35444200 DOI: 10.1038/s41467-022-29688-5
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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