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Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box

Author

Listed:
  • Janette Reader

    (University of Pretoria)

  • Mariëtte E. van der Watt

    (University of Pretoria)

  • Dale Taylor

    (University of Cape Town)

  • Claire Le Manach

    (University of Cape Town)

  • Nimisha Mittal

    (University of California San Diego)

  • Sabine Ottilie

    (University of California San Diego)

  • Anjo Theron

    (Council for Scientific and Industrial Research)

  • Phanankosi Moyo

    (University of Pretoria)

  • Erica Erlank

    (University of the Witwatersrand, and Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service)

  • Luisa Nardini

    (University of the Witwatersrand, and Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service)

  • Nelius Venter

    (University of the Witwatersrand, and Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service)

  • Sonja Lauterbach

    (University of the Witwatersrand)

  • Belinda Bezuidenhout

    (University of the Witwatersrand)

  • Andre Horatscheck

    (University of Cape Town)

  • Ashleigh van Heerden

    (University of Pretoria)

  • Natalie J. Spillman

    (Washington University)

  • Anne N. Cowell

    (University of California San Diego)

  • Jessica Connacher

    (University of Pretoria)

  • Daniel Opperman

    (University of Pretoria)

  • Lindsey M. Orchard

    (Pennsylvania State University)

  • Manuel Llinás

    (Pennsylvania State University
    Pennsylvania State University)

  • Eva S. Istvan

    (Washington University)

  • Daniel E. Goldberg

    (Washington University)

  • Grant A. Boyle

    (University of Cape Town)

  • David Calvo

    (GlaxoSmithKline (GSK))

  • Dalu Mancama

    (Council for Scientific and Industrial Research)

  • Theresa L. Coetzer

    (University of the Witwatersrand)

  • Elizabeth A. Winzeler

    (University of California San Diego)

  • James Duffy

    (International Center Cointrin)

  • Lizette L. Koekemoer

    (University of the Witwatersrand, and Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service)

  • Gregory Basarab

    (University of Cape Town)

  • Kelly Chibale

    (University of Cape Town
    University of Cape Town)

  • Lyn-Marié Birkholtz

    (University of Pretoria)

Abstract

Chemical matter is needed to target the divergent biology associated with the different life cycle stages of Plasmodium. Here, we report the parallel de novo screening of the Medicines for Malaria Venture (MMV) Pandemic Response Box against Plasmodium asexual and liver stage parasites, stage IV/V gametocytes, gametes, oocysts and as endectocides. Unique chemotypes were identified with both multistage activity or stage-specific activity, including structurally diverse gametocyte-targeted compounds with potent transmission-blocking activity, such as the JmjC inhibitor ML324 and the antitubercular clinical candidate SQ109. Mechanistic investigations prove that ML324 prevents histone demethylation, resulting in aberrant gene expression and death in gametocytes. Moreover, the selection of parasites resistant to SQ109 implicates the druggable V-type H+-ATPase for the reduced sensitivity. Our data therefore provides an expansive dataset of compounds that could be redirected for antimalarial development and also point towards proteins that can be targeted in multiple parasite life cycle stages.

Suggested Citation

  • Janette Reader & Mariëtte E. van der Watt & Dale Taylor & Claire Le Manach & Nimisha Mittal & Sabine Ottilie & Anjo Theron & Phanankosi Moyo & Erica Erlank & Luisa Nardini & Nelius Venter & Sonja Laut, 2021. "Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20629-8
    DOI: 10.1038/s41467-020-20629-8
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    Cited by:

    1. Mariska Naude & Ashleigh van Heerden & Janette Reader & Mariëtte van der Watt & Jandeli Niemand & Dorè Joubert & Giulia Siciliano & Pietro Alano & Mathew Njoroge & Kelly Chibale & Esperanza Herreros &, 2024. "Eliminating malaria transmission requires targeting immature and mature gametocytes through lipoidal uptake of antimalarials," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Thaila Fernanda Reis & Patrícia Alves Castro & Rafael Wesley Bastos & Camila Figueiredo Pinzan & Pedro F. N. Souza & Suzanne Ackloo & Mohammad Anwar Hossain & David Harold Drewry & Sondus Alkhazraji &, 2023. "A host defense peptide mimetic, brilacidin, potentiates caspofungin antifungal activity against human pathogenic fungi," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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