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A novel multiple-stage antimalarial agent that inhibits protein synthesis

Author

Listed:
  • Beatriz Baragaña

    (Drug Discovery Unit, College of Life Sciences, University of Dundee)

  • Irene Hallyburton

    (Drug Discovery Unit, College of Life Sciences, University of Dundee)

  • Marcus C. S. Lee

    (Columbia University College of Physicians and Surgeons
    † Present address: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.)

  • Neil R. Norcross

    (Drug Discovery Unit, College of Life Sciences, University of Dundee)

  • Raffaella Grimaldi

    (Drug Discovery Unit, College of Life Sciences, University of Dundee)

  • Thomas D. Otto

    (Malaria Programme, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • William R. Proto

    (Malaria Programme, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • Andrew M. Blagborough

    (Imperial College)

  • Stephan Meister

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

  • Grennady Wirjanata

    (Menzies School of Health Research, Charles Darwin University)

  • Andrea Ruecker

    (Imperial College)

  • Leanna M. Upton

    (Imperial College)

  • Tara S. Abraham

    (Columbia University College of Physicians and Surgeons)

  • Mariana J. Almeida

    (Columbia University College of Physicians and Surgeons)

  • Anupam Pradhan

    (College of Public Health University of South Florida)

  • Achim Porzelle

    (Drug Discovery Unit, College of Life Sciences, University of Dundee)

  • María Santos Martínez

    (GlaxoSmithKline, Tres Cantos Medicines Development Campus-Diseases of the Developing World)

  • Judith M. Bolscher

    (TropIQ Health Sciences)

  • Andrew Woodland

    (Drug Discovery Unit, College of Life Sciences, University of Dundee)

  • Torsten Luksch

    (Drug Discovery Unit, College of Life Sciences, University of Dundee)

  • Suzanne Norval

    (Drug Discovery Unit, College of Life Sciences, University of Dundee)

  • Fabio Zuccotto

    (Drug Discovery Unit, College of Life Sciences, University of Dundee)

  • John Thomas

    (Drug Discovery Unit, College of Life Sciences, University of Dundee)

  • Frederick Simeons

    (Drug Discovery Unit, College of Life Sciences, University of Dundee)

  • Laste Stojanovski

    (Drug Discovery Unit, College of Life Sciences, University of Dundee)

  • Maria Osuna-Cabello

    (Drug Discovery Unit, College of Life Sciences, University of Dundee)

  • Paddy M. Brock

    (Imperial College)

  • Tom S. Churcher

    (Imperial College)

  • Katarzyna A. Sala

    (Imperial College)

  • Sara E. Zakutansky

    (Imperial College)

  • María Belén Jiménez-Díaz

    (GlaxoSmithKline, Tres Cantos Medicines Development Campus-Diseases of the Developing World)

  • Laura Maria Sanz

    (GlaxoSmithKline, Tres Cantos Medicines Development Campus-Diseases of the Developing World)

  • Jennifer Riley

    (Drug Discovery Unit, College of Life Sciences, University of Dundee)

  • Rajshekhar Basak

    (Columbia University College of Physicians and Surgeons)

  • Michael Campbell

    (Centre for Drug Candidate Optimisation, Monash University)

  • Vicky M. Avery

    (Eskitis Institute, Brisbane Innovation Park, Nathan Campus, Griffith University)

  • Robert W. Sauerwein

    (TropIQ Health Sciences)

  • Koen J. Dechering

    (TropIQ Health Sciences)

  • Rintis Noviyanti

    (Malaria Pathogenesis Laboratory, Eijkman Institute for Molecular Biology)

  • Brice Campo

    (Medicines for Malaria Venture)

  • Julie A. Frearson

    (Drug Discovery Unit, College of Life Sciences, University of Dundee)

  • Iñigo Angulo-Barturen

    (GlaxoSmithKline, Tres Cantos Medicines Development Campus-Diseases of the Developing World)

  • Santiago Ferrer-Bazaga

    (GlaxoSmithKline, Tres Cantos Medicines Development Campus-Diseases of the Developing World)

  • Francisco Javier Gamo

    (GlaxoSmithKline, Tres Cantos Medicines Development Campus-Diseases of the Developing World)

  • Paul G. Wyatt

    (Drug Discovery Unit, College of Life Sciences, University of Dundee)

  • Didier Leroy

    (Medicines for Malaria Venture)

  • Peter Siegl

    (Medicines for Malaria Venture)

  • Michael J. Delves

    (Imperial College)

  • Dennis E. Kyle

    (College of Public Health University of South Florida)

  • Sergio Wittlin

    (Swiss Tropical and Public Health Institute)

  • Jutta Marfurt

    (Menzies School of Health Research, Charles Darwin University)

  • Ric N. Price

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

  • Robert E. Sinden

    (Imperial College)

  • Elizabeth A. Winzeler

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

  • Susan A. Charman

    (Centre for Drug Candidate Optimisation, Monash University)

  • Lidiya Bebrevska

    (Medicines for Malaria Venture)

  • David W. Gray

    (Drug Discovery Unit, College of Life Sciences, University of Dundee)

  • Simon Campbell

    (Medicines for Malaria Venture)

  • Alan H. Fairlamb

    (Drug Discovery Unit, College of Life Sciences, University of Dundee)

  • Paul A. Willis

    (Medicines for Malaria Venture)

  • Julian C. Rayner

    (Malaria Programme, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • David A. Fidock

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

  • Kevin D. Read

    (Drug Discovery Unit, College of Life Sciences, University of Dundee)

  • Ian H. Gilbert

    (Drug Discovery Unit, College of Life Sciences, University of Dundee)

Abstract

There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.

Suggested Citation

  • Beatriz Baragaña & Irene Hallyburton & Marcus C. S. Lee & Neil R. Norcross & Raffaella Grimaldi & Thomas D. Otto & William R. Proto & Andrew M. Blagborough & Stephan Meister & Grennady Wirjanata & And, 2015. "A novel multiple-stage antimalarial agent that inhibits protein synthesis," Nature, Nature, vol. 522(7556), pages 315-320, June.
    • Handle: RePEc:nat:nature:v:522:y:2015:i:7556:d:10.1038_nature14451
    DOI: 10.1038/nature14451
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