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A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance

Author

Listed:
  • Paul M. O’Neill

    (University of Liverpool
    School of Biomedical Sciences, MRC Centre for Drug Safety Science, University of Liverpool)

  • Richard K. Amewu

    (University of Liverpool
    Present address: Department of Chemistry, University of Ghana, P.O. Box LG56, Legon, Accra, Ghana)

  • Susan A. Charman

    (Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University)

  • Sunil Sabbani

    (University of Liverpool)

  • Nina F. Gnädig

    (Columbia University College of Physicians and Surgeons)

  • Judith Straimer

    (Columbia University College of Physicians and Surgeons)

  • David A. Fidock

    (Columbia University College of Physicians and Surgeons
    Columbia University Medical Center)

  • Emma R. Shore

    (University of Liverpool)

  • Natalie L. Roberts

    (University of Liverpool)

  • Michael H.-L. Wong

    (University of Liverpool)

  • W. David Hong

    (University of Liverpool)

  • Chandrakala Pidathala

    (University of Liverpool)

  • Chris Riley

    (University of Liverpool)

  • Ben Murphy

    (University of Liverpool)

  • Ghaith Aljayyoussi

    (Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine)

  • Francisco Javier Gamo

    (Tres Cantos Medicines Development Campus)

  • Laura Sanz

    (Tres Cantos Medicines Development Campus)

  • Janneth Rodrigues

    (Tres Cantos Medicines Development Campus)

  • Carolina Gonzalez Cortes

    (Tres Cantos Medicines Development Campus)

  • Esperanza Herreros

    (Tres Cantos Medicines Development Campus)

  • Iñigo Angulo-Barturén

    (Tres Cantos Medicines Development Campus)

  • María Belén Jiménez-Díaz

    (Tres Cantos Medicines Development Campus)

  • Santiago Ferrer Bazaga

    (Tres Cantos Medicines Development Campus)

  • María Santos Martínez-Martínez

    (Tres Cantos Medicines Development Campus)

  • Brice Campo

    (Medicines for Malaria Venture, ICC)

  • Raman Sharma

    (Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine)

  • Eileen Ryan

    (Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University)

  • David M. Shackleford

    (Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University)

  • Simon Campbell

    (Medicines for Malaria Venture, ICC)

  • Dennis A. Smith

    (Medicines for Malaria Venture, ICC)

  • Grennady Wirjanata

    (Menzies School of Health Research, Charles Darwin University)

  • Rintis Noviyanti

    (Eijkman Institute for Molecular Biology)

  • Ric N. Price

    (Menzies School of Health Research, Charles Darwin University
    Centre for Tropical Medicine and Global Health, University of Oxford)

  • Jutta Marfurt

    (Menzies School of Health Research, Charles Darwin University)

  • Michael J. Palmer

    (Medicines for Malaria Venture, ICC)

  • Ian M. Copple

    (School of Biomedical Sciences, MRC Centre for Drug Safety Science, University of Liverpool)

  • Amy E. Mercer

    (School of Biomedical Sciences, MRC Centre for Drug Safety Science, University of Liverpool)

  • Andrea Ruecker

    (Imperial College London)

  • Michael J. Delves

    (Imperial College London)

  • Robert E. Sinden

    (Imperial College London
    The Jenner Institute, University of Oxford)

  • Peter Siegl

    (Medicines for Malaria Venture, ICC)

  • Jill Davies

    (Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine
    Present address: Department of Chemistry, University of Ghana, P.O. Box LG56, Legon, Accra, Ghana)

  • Rosemary Rochford

    (University of Colorado)

  • Clemens H. M. Kocken

    (Biomedical Primate Research Centre)

  • Anne-Marie Zeeman

    (Biomedical Primate Research Centre)

  • Gemma L. Nixon

    (University of Liverpool)

  • Giancarlo A. Biagini

    (Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine)

  • Stephen A. Ward

    (Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine)

Abstract

K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives.

Suggested Citation

  • Paul M. O’Neill & Richard K. Amewu & Susan A. Charman & Sunil Sabbani & Nina F. Gnädig & Judith Straimer & David A. Fidock & Emma R. Shore & Natalie L. Roberts & Michael H.-L. Wong & W. David Hong & C, 2017. "A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance," Nature Communications, Nature, vol. 8(1), pages 1-10, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15159
    DOI: 10.1038/ncomms15159
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