title: A novel multiple-stage antimalarial agent that inhibits protein synthesis.
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.
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Baragaña
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Irene
authors.initials: I
authors.lastname: Hallyburton
authors.affiliation: Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
authors.forename: Marcus C S
authors.initials: MC
authors.lastname: Lee
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Norcross
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Grimaldi
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Otto
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: William R
authors.initials: WR
authors.lastname: Proto
authors.affiliation: Department of Life Sciences, Imperial College, London SW7 2AZ, UK.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Blagborough
authors.affiliation: University of California, San Diego, School of Medicine, 9500 Gilman Drive 0760, La Jolla, California 92093, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Meister
authors.affiliation: Global Health and Tropical Medicine Division, Menzies School of Health Research, Charles Darwin University, PO Box 41096, Casuarina, Darwin, Northern Territory 0811, Australia.
authors.forename: Grennady
authors.initials: G
authors.lastname: Wirjanata
authors.affiliation: Department of Life Sciences, Imperial College, London SW7 2AZ, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ruecker
authors.affiliation: Department of Life Sciences, Imperial College, London SW7 2AZ, UK.
authors.forename: Leanna M
authors.initials: LM
authors.lastname: Upton
authors.affiliation: Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
authors.forename: Tara S
authors.initials: TS
authors.lastname: Abraham
authors.affiliation: Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
authors.forename: Mariana J
authors.initials: MJ
authors.lastname: Almeida
authors.affiliation: Department of Global Health, College of Public Health University of South Florida, 3720 Spectrum Boulevard, Suite 304, Tampa, Florida 33612, USA.
authors.forename: Anupam
authors.initials: A
authors.lastname: Pradhan
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Achim
authors.initials: A
authors.lastname: Porzelle
authors.forename: Torsten
authors.lastname: Luksch
authors.affiliation: GlaxoSmithKline, Tres Cantos Medicines Development Campus-Diseases of the Developing World, Severo Ochoa 2, Tres Cantos 28760, Madrid, Spain.
authors.forename: María Santos
authors.initials: MS
authors.lastname: Martínez
authors.forename: Torsten
authors.initials: T
authors.lastname: Luksch
authors.affiliation: TropIQ Health Sciences, Geert Grooteplein 28, Huispost 268, 6525 GA Nijmegen, The Netherlands.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Bolscher
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Woodland
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Norval
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Fabio
authors.initials: F
authors.lastname: Zuccotto
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: John
authors.initials: J
authors.lastname: Thomas
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Frederick
authors.initials: F
authors.lastname: Simeons
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Laste
authors.initials: L
authors.lastname: Stojanovski
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Osuna-Cabello
authors.affiliation: Department of Life Sciences, Imperial College, London SW7 2AZ, UK.
authors.forename: Paddy M
authors.initials: PM
authors.lastname: Brock
authors.affiliation: Department of Life Sciences, Imperial College, London SW7 2AZ, UK.
authors.forename: Tom S
authors.initials: TS
authors.lastname: Churcher
authors.affiliation: Department of Life Sciences, Imperial College, London SW7 2AZ, UK.
authors.forename: Katarzyna A
authors.initials: KA
authors.lastname: Sala
authors.affiliation: Department of Life Sciences, Imperial College, London SW7 2AZ, UK.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Zakutansky
authors.affiliation: GlaxoSmithKline, Tres Cantos Medicines Development Campus-Diseases of the Developing World, Severo Ochoa 2, Tres Cantos 28760, Madrid, Spain.
authors.forename: María Belén
authors.initials: MB
authors.lastname: Jiménez-Díaz
authors.affiliation: GlaxoSmithKline, Tres Cantos Medicines Development Campus-Diseases of the Developing World, Severo Ochoa 2, Tres Cantos 28760, Madrid, Spain.
authors.forename: Laura Maria
authors.initials: LM
authors.lastname: Sanz
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Riley
authors.affiliation: Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
authors.forename: Rajshekhar
authors.initials: R
authors.lastname: Basak
authors.affiliation: Centre for Drug Candidate Optimisation, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Campbell
authors.affiliation: Eskitis Institute, Brisbane Innovation Park, Nathan Campus, Griffith University, Queensland 4111, Australia.
authors.forename: Vicky M
authors.initials: VM
authors.lastname: Avery
authors.affiliation: TropIQ Health Sciences, Geert Grooteplein 28, Huispost 268, 6525 GA Nijmegen, The Netherlands.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sauerwein
authors.affiliation: TropIQ Health Sciences, Geert Grooteplein 28, Huispost 268, 6525 GA Nijmegen, The Netherlands.
authors.forename: Koen J
authors.initials: KJ
authors.lastname: Dechering
authors.affiliation: Malaria Pathogenesis Laboratory, Eijkman Institute for Molecular Biology, Jalan Diponegoro 69, 10430 Jakarta, Indonesia.
authors.forename: Rintis
authors.initials: R
authors.lastname: Noviyanti
authors.affiliation: Medicines for Malaria Venture, PO Box 1826, 20 route de Pre-Bois, 1215 Geneva 15, Switzerland.
authors.forename: Brice
authors.initials: B
authors.lastname: Campo
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Frearson
authors.affiliation: GlaxoSmithKline, Tres Cantos Medicines Development Campus-Diseases of the Developing World, Severo Ochoa 2, Tres Cantos 28760, Madrid, Spain.
authors.forename: Iñigo
authors.initials: I
authors.lastname: Angulo-Barturen
authors.affiliation: GlaxoSmithKline, Tres Cantos Medicines Development Campus-Diseases of the Developing World, Severo Ochoa 2, Tres Cantos 28760, Madrid, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Ferrer-Bazaga
authors.affiliation: GlaxoSmithKline, Tres Cantos Medicines Development Campus-Diseases of the Developing World, Severo Ochoa 2, Tres Cantos 28760, Madrid, Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Gamo
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Wyatt
authors.affiliation: Medicines for Malaria Venture, PO Box 1826, 20 route de Pre-Bois, 1215 Geneva 15, Switzerland.
authors.forename: Didier
authors.initials: D
authors.lastname: Leroy
authors.affiliation: Medicines for Malaria Venture, PO Box 1826, 20 route de Pre-Bois, 1215 Geneva 15, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Siegl
authors.affiliation: Department of Life Sciences, Imperial College, London SW7 2AZ, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Delves
authors.affiliation: Department of Global Health, College of Public Health University of South Florida, 3720 Spectrum Boulevard, Suite 304, Tampa, Florida 33612, USA.
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Kyle
authors.affiliation: Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051 Basel, Switzerland.
authors.forename: Sergio
authors.initials: S
authors.lastname: Wittlin
authors.affiliation: Global Health and Tropical Medicine Division, Menzies School of Health Research, Charles Darwin University, PO Box 41096, Casuarina, Darwin, Northern Territory 0811, Australia.
authors.forename: Jutta
authors.initials: J
authors.lastname: Marfurt
authors.affiliation: 1] Global Health and Tropical Medicine Division, Menzies School of Health Research, Charles Darwin University, PO Box 41096, Casuarina, Darwin, Northern Territory 0811, Australia [2] Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7LJ, UK.
authors.forename: Ric N
authors.initials: RN
authors.lastname: Price
authors.affiliation: Department of Life Sciences, Imperial College, London SW7 2AZ, UK.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Sinden
authors.affiliation: University of California, San Diego, School of Medicine, 9500 Gilman Drive 0760, La Jolla, California 92093, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Winzeler
authors.affiliation: Centre for Drug Candidate Optimisation, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.affiliation: Medicines for Malaria Venture, PO Box 1826, 20 route de Pre-Bois, 1215 Geneva 15, Switzerland.
authors.forename: Lidiya
authors.initials: L
authors.lastname: Bebrevska
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: David W
authors.initials: DW
authors.lastname: Gray
authors.affiliation: Medicines for Malaria Venture, PO Box 1826, 20 route de Pre-Bois, 1215 Geneva 15, Switzerland.
authors.forename: Simon
authors.initials: S
authors.lastname: Campbell
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Fairlamb
authors.affiliation: Medicines for Malaria Venture, PO Box 1826, 20 route de Pre-Bois, 1215 Geneva 15, Switzerland.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Willis
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Julian C
authors.initials: JC
authors.lastname: Rayner
authors.affiliation: 1] Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA [2] Division of Infectious Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Fidock
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Read
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D055808:Drug Discovery; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D008018:Life Cycle Stages / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000469:parasitology; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology*; D008297:Male; D008958:Models, Molecular; D020652:Peptide Elongation Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010961:Plasmodium / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D010962:Plasmodium berghei / Q000187:drug effects / Q000502:physiology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000378:metabolism; D010966:Plasmodium vivax / Q000187:drug effects / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects*; D011804:Quinolines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; C000599320:DDD107498; D020652:Peptide Elongation Factor 2; D011804:Quinolines