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Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

Author

Listed:
  • Laura E. Vries

    (Radboud Institute for Molecular Life Sciences, Radboud University Medical Center
    Harvard T.H. Chan School of Public Health)

  • 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
    Institut Pasteur, Paris & Institut Pasteur du Cambodge)

  • Laura M. Sanz

    (Global Health, GlaxoSmithKline)

  • Graham Trevitt

    (Sygnature Discovery)

  • Benoit Witkowski

    (Institut Pasteur du Cambodge
    Institut Pasteur, Paris & Institut Pasteur du Cambodge)

  • Sergio Wittlin

    (Swiss Tropical and Public Health Institute
    University of Basel)

  • 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
    TropIQ Health Sciences)

  • 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
    Columbia University Irving Medical Center)

  • Manuel Llinás

    (The Pennsylvania State University
    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)

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.

Suggested Citation

  • 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. Bo, 2022. "Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29688-5
    DOI: 10.1038/s41467-022-29688-5
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    References listed on IDEAS

    as
    1. Suresh M. Ganesan & Alejandra Falla & Stephen J. Goldfless & Armiyaw S. Nasamu & Jacquin C. Niles, 2016. "Synthetic RNA–protein modules integrated with native translation mechanisms to control gene expression in malaria parasites," Nature Communications, Nature, vol. 7(1), pages 1-10, April.
    2. Michael J. Delves & Celia Miguel-Blanco & Holly Matthews & Irene Molina & Andrea Ruecker & Sabrina Yahiya & Ursula Straschil & Matthew Abraham & María Luisa León & Oliver J. Fischer & Ainoa Rueda-Zubi, 2018. "A high throughput screen for next-generation leads targeting malaria parasite transmission," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
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    Cited by:

    1. Selina Bopp & Charisse Flerida A. Pasaje & Robert L. Summers & Pamela Magistrado-Coxen & Kyra A. Schindler & Victoriano Corpas-Lopez & Tomas Yeo & Sachel Mok & Sumanta Dey & Sebastian Smick & Armiyaw , 2023. "Potent acyl-CoA synthetase 10 inhibitors kill Plasmodium falciparum by disrupting triglyceride formation," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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