A novel multiple-stage antimalarial agent that inhibits protein synthesis

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, Andrea Ruecker, Leanna M. Upton, Tara S. Abraham, Mariana J. Almeida, Anupam Pradhan, Achim Porzelle, María Santos Martínez, Judith M. Bolscher, Andrew Woodland, Torsten Luksch, Suzanne Norval, Fabio Zuccotto, John Thomas, Frederick Simeons, Laste Stojanovski, Maria Osuna-Cabello, Paddy M. Brock, Tom S. Churcher, Katarzyna A. Sala, Sara E. Zakutansky, María Belén Jiménez-Díaz, Laura Maria Sanz, Jennifer Riley, Rajshekhar Basak, Michael Campbell, Vicky M. Avery, Robert W. Sauerwein, Koen J. Dechering, Rintis Noviyanti, Brice Campo, Julie A. Frearson, Iñigo Angulo-Barturen, Santiago Ferrer-Bazaga, Francisco Javier Gamo, Paul G. Wyatt, Didier Leroy, Peter Siegl, Michael J. Delves, Dennis E. Kyle, Sergio Wittlin, Jutta Marfurt, Ric N. Price, Robert E. Sinden, Elizabeth A. Winzeler, Susan A. Charman, Lidiya Bebrevska, David W. Gray, Simon Campbell, Alan H. Fairlamb, Paul A. Willis, Julian C. Rayner, David A. Fidock, Kevin D. Read () and Ian H. Gilbert ()
Additional contact information
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
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
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
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

Nature, 2015, vol. 522, issue 7556, 315-320

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature14451

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