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Esterase mutation is a mechanism of resistance to antimalarial compounds

Author

Listed:
  • Eva S. Istvan

    (Washington University School of Medicine
    Washington University School of Medicine)

  • Jeremy P. Mallari

    (Washington University School of Medicine
    Washington University School of Medicine
    Present address: Department of Chemistry and Biochemistry, California State University, San Bernardino, California 92407, USA)

  • Victoria C. Corey

    (School of Medicine, University of California San Diego School of Medicine)

  • Neekesh V. Dharia

    (School of Medicine, University of California San Diego School of Medicine
    Present address: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children’s Hospital, Boston, Massachusetts 02215, USA)

  • Garland R. Marshall

    (Washington University School of Medicine)

  • Elizabeth A. Winzeler

    (School of Medicine, University of California San Diego School of Medicine)

  • Daniel E. Goldberg

    (Washington University School of Medicine
    Washington University School of Medicine)

Abstract

Pepstatin is a potent peptidyl inhibitor of various malarial aspartic proteases, and also has parasiticidal activity. Activity of pepstatin against cultured Plasmodium falciparum is highly variable depending on the commercial source. Here we identify a minor contaminant (pepstatin butyl ester) as the active anti-parasitic principle. We synthesize a series of derivatives and characterize an analogue (pepstatin hexyl ester) with low nanomolar activity. By selecting resistant parasite mutants, we find that a parasite esterase, PfPARE (P. falciparum Prodrug Activation and Resistance Esterase) is required for activation of esterified pepstatin. Parasites with esterase mutations are resistant to pepstatin esters and to an open source antimalarial compound, MMV011438. Recombinant PfPARE hydrolyses pepstatin esters and de-esterifies MMV011438. We conclude that (1) pepstatin is a potent but poorly bioavailable antimalarial; (2) PfPARE is a functional esterase that is capable of activating prodrugs; (3) Mutations in PfPARE constitute a mechanism of antimalarial resistance.

Suggested Citation

  • Eva S. Istvan & Jeremy P. Mallari & Victoria C. Corey & Neekesh V. Dharia & Garland R. Marshall & Elizabeth A. Winzeler & Daniel E. Goldberg, 2017. "Esterase mutation is a mechanism of resistance to antimalarial compounds," Nature Communications, Nature, vol. 8(1), pages 1-8, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14240
    DOI: 10.1038/ncomms14240
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    Cited by:

    1. Sumit Mukherjee & Suong Nguyen & Eashan Sharma & Daniel E. Goldberg, 2022. "Maturation and substrate processing topography of the Plasmodium falciparum invasion/egress protease plasmepsin X," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Krittikorn Kümpornsin & Theerarat Kochakarn & Tomas Yeo & John Okombo & Madeline R. Luth & Johanna Hoshizaki & Mukul Rawat & Richard D. Pearson & Kyra A. Schindler & Sachel Mok & Heekuk Park & Anne-Ca, 2023. "Generation of a mutator parasite to drive resistome discovery in Plasmodium falciparum," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Patrick K. Tumwebaze & Melissa D. Conrad & Martin Okitwi & Stephen Orena & Oswald Byaruhanga & Thomas Katairo & Jennifer Legac & Shreeya Garg & David Giesbrecht & Sawyer R. Smith & Frida G. Ceja & Sam, 2022. "Decreased susceptibility of Plasmodium falciparum to both dihydroartemisinin and lumefantrine in northern Uganda," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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