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Safe drugs with high potential to block malaria transmission revealed by a spleen-mimetic screening

Author

Listed:
  • Mario Carucci

    (Université Paris Cité, Inserm, UMR-1134, Biologie Intégré du Globule Rouge)

  • Julien Duez

    (SYNSIGHT)

  • Joel Tarning

    (Mahidol University
    University of Oxford)

  • Irene García-Barbazán

    (Mycology Reference Laboratory, National Centre for Microbiology, Instituto de Salud Carlos III)

  • Aurélie Fricot-Monsinjon

    (Université Paris Cité, Inserm, UMR-1134, Biologie Intégré du Globule Rouge)

  • Abdoulaye Sissoko

    (Université Paris Cité, Inserm, UMR-1134, Biologie Intégré du Globule Rouge)

  • Lucie Dumas

    (Université Paris Cité, Inserm, UMR-1134, Biologie Intégré du Globule Rouge)

  • Pablo Gamallo

    (Global Health Medicines R&D, GlaxoSmith Kline (GSK))

  • Babette Beher

    (Université Paris Cité, Inserm, UMR-1134, Biologie Intégré du Globule Rouge)

  • Pascal Amireault

    (Université Paris Cité, Inserm, UMR-1134, Biologie Intégré du Globule Rouge
    Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutic implications, INSERM)

  • Michael Dussiot

    (Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutic implications, INSERM
    Laboratoire d’Excellence GR-Ex)

  • Ming Dao

    (Massachusetts Institute of Technology)

  • Mitchell V. Hull

    (Calibr, a division of The Scripps Research Institute)

  • Case W. McNamara

    (Calibr, a division of The Scripps Research Institute)

  • Camille Roussel

    (Université Paris Cité, Inserm, UMR-1134, Biologie Intégré du Globule Rouge
    Laboratoire d’Excellence GR-Ex
    Laboratoire d’Hématologie générale, Hôpital Universitaire Necker Enfants Malades, Assistance Publique–Hôpitaux de Paris (AP-HP))

  • Papa Alioune Ndour

    (Université Paris Cité, Inserm, UMR-1134, Biologie Intégré du Globule Rouge)

  • Laura Maria Sanz

    (Global Health Medicines R&D, GlaxoSmith Kline (GSK))

  • Francisco Javier Gamo

    (Global Health Medicines R&D, GlaxoSmith Kline (GSK))

  • Pierre Buffet

    (Université Paris Cité, Inserm, UMR-1134, Biologie Intégré du Globule Rouge
    AP-HP, Necker Hospital
    Centre Médical de l’Institut Pasteur (CMIP), Institut Pasteur)

Abstract

Malaria parasites like Plasmodium falciparum multiply in red blood cells (RBC), which are cleared from the bloodstream by the spleen when their deformability is altered. Drug-induced stiffening of Plasmodium falciparum-infected RBC should therefore induce their elimination from the bloodstream. Here, based on this original mechanical approach, we identify safe drugs with strong potential to block the malaria transmission. By screening 13 555 compounds with spleen-mimetic microfilters, we identified 82 that target circulating transmissible form of P. falciparum. NITD609, an orally administered PfATPase inhibitor with known effects on P. falciparum, killed and stiffened transmission stages in vitro at nanomolar concentrations. Short exposures to TD-6450, an orally-administered NS5A hepatitis C virus inhibitor, stiffened transmission parasite stages and killed asexual stages in vitro at high nanomolar concentrations. A Phase 1 study in humans with a primary safety outcome and a secondary pharmacokinetics outcome ( https://clinicaltrials.gov , ID: NCT02022306) showed no severe adverse events either with single or multiple doses. Pharmacokinetic modelling showed that these concentrations can be reached in the plasma of subjects receiving short courses of TD-6450. This physiologically relevant screen identified multiple mechanisms of action, and safe drugs with strong potential as malaria transmission-blocking agents which could be rapidly tested in clinical trials.

Suggested Citation

  • Mario Carucci & Julien Duez & Joel Tarning & Irene García-Barbazán & Aurélie Fricot-Monsinjon & Abdoulaye Sissoko & Lucie Dumas & Pablo Gamallo & Babette Beher & Pascal Amireault & Michael Dussiot & M, 2023. "Safe drugs with high potential to block malaria transmission revealed by a spleen-mimetic screening," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37359-2
    DOI: 10.1038/s41467-023-37359-2
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    References listed on IDEAS

    as
    1. Prasanna Jagannathan & Abel Kakuru, 2022. "Malaria in 2022: Increasing challenges, cautious optimism," Nature Communications, Nature, vol. 13(1), pages 1-3, December.
    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.
    3. Akhil B. Vaidya & Joanne M. Morrisey & Zhongsheng Zhang & Sudipta Das & Thomas M. Daly & Thomas D. Otto & Natalie J. Spillman & Matthew Wyvratt & Peter Siegl & Jutta Marfurt & Grennady Wirjanata & Bon, 2014. "Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum," Nature Communications, Nature, vol. 5(1), pages 1-10, December.
    Full references (including those not matched with items on IDEAS)

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