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Aryl amino acetamides prevent Plasmodium falciparum ring development via targeting the lipid-transfer protein PfSTART1

Author

Listed:
  • Madeline G. Dans

    (Burnet Institute
    Walter and Eliza Hall Institute
    Deakin University
    The University of Melbourne)

  • Coralie Boulet

    (Burnet Institute
    University of Geneva)

  • Gabrielle M. Watson

    (Walter and Eliza Hall Institute
    The University of Melbourne)

  • William Nguyen

    (Walter and Eliza Hall Institute
    The University of Melbourne)

  • Jerzy M. Dziekan

    (Walter and Eliza Hall Institute
    The University of Melbourne)

  • Cindy Evelyn

    (Walter and Eliza Hall Institute
    The University of Melbourne)

  • Kitsanapong Reaksudsan

    (Walter and Eliza Hall Institute
    The University of Melbourne)

  • Somya Mehra

    (Burnet Institute
    Deakin University)

  • Zahra Razook

    (Burnet Institute
    Deakin University)

  • Niall D. Geoghegan

    (Walter and Eliza Hall Institute
    The University of Melbourne)

  • Michael J. Mlodzianoski

    (Walter and Eliza Hall Institute
    The University of Melbourne)

  • Christopher Dean Goodman

    (The University of Melbourne)

  • Dawson B. Ling

    (Burnet Institute)

  • Thorey K. Jonsdottir

    (Burnet Institute
    The University of Melbourne
    Umeå University
    The Laboratory for Molecular Infection Medicine Sweden (MIMS))

  • Joshua Tong

    (Walter and Eliza Hall Institute)

  • Mufuliat Toyin Famodimu

    (London School of Hygiene and Tropical Medicine)

  • Mojca Kristan

    (London School of Hygiene & Tropical Medicine)

  • Harry Pollard

    (London School of Hygiene & Tropical Medicine)

  • Lindsay B. Stewart

    (London School of Hygiene & Tropical Medicine)

  • Luke Brandner-Garrod

    (London School of Hygiene & Tropical Medicine)

  • Colin J. Sutherland

    (London School of Hygiene and Tropical Medicine
    London School of Hygiene & Tropical Medicine)

  • Michael J. Delves

    (London School of Hygiene and Tropical Medicine)

  • Geoffrey I. McFadden

    (The University of Melbourne)

  • Alyssa E. Barry

    (Burnet Institute
    Deakin University)

  • Brendan S. Crabb

    (Burnet Institute
    The University of Melbourne
    Monash University)

  • Tania F. Koning-Ward

    (Deakin University)

  • Kelly L. Rogers

    (Walter and Eliza Hall Institute
    The University of Melbourne)

  • Alan F. Cowman

    (Walter and Eliza Hall Institute
    The University of Melbourne)

  • Wai-Hong Tham

    (Walter and Eliza Hall Institute
    The University of Melbourne)

  • Brad E. Sleebs

    (Walter and Eliza Hall Institute
    The University of Melbourne)

  • Paul R. Gilson

    (Burnet Institute
    The University of Melbourne)

Abstract

With resistance to most antimalarials increasing, it is imperative that new drugs are developed. We previously identified an aryl acetamide compound, MMV006833 (M-833), that inhibited the ring-stage development of newly invaded merozoites. Here, we select parasites resistant to M-833 and identify mutations in the START lipid transfer protein (PF3D7_0104200, PfSTART1). Introducing PfSTART1 mutations into wildtype parasites reproduces resistance to M-833 as well as to more potent analogues. PfSTART1 binding to the analogues is validated using organic solvent-based Proteome Integral Solubility Alteration (Solvent PISA) assays. Imaging of invading merozoites shows the inhibitors prevent the development of ring-stage parasites potentially by inhibiting the expansion of the encasing parasitophorous vacuole membrane. The PfSTART1-targeting compounds also block transmission to mosquitoes and with multiple stages of the parasite’s lifecycle being affected, PfSTART1 represents a drug target with a new mechanism of action.

Suggested Citation

  • Madeline G. Dans & Coralie Boulet & Gabrielle M. Watson & William Nguyen & Jerzy M. Dziekan & Cindy Evelyn & Kitsanapong Reaksudsan & Somya Mehra & Zahra Razook & Niall D. Geoghegan & Michael J. Mlodz, 2024. "Aryl amino acetamides prevent Plasmodium falciparum ring development via targeting the lipid-transfer protein PfSTART1," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49491-8
    DOI: 10.1038/s41467-024-49491-8
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