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; Torsten Luksch; María Santos Martínez; Torsten Luksch; Judith M Bolscher; Andrew Woodland; 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; Ian H Gilbert

doi:10.1038/nature14451

A novel multiple-stage antimalarial agent that inhibits protein synthesis

Nature. 2015 Jun 18;522(7556):315-20. doi: 10.1038/nature14451.

Authors

Beatriz Baragaña¹, Irene Hallyburton¹, Marcus C S Lee², Neil R Norcross¹, Raffaella Grimaldi¹, Thomas D Otto³, William R Proto³, Andrew M Blagborough⁴, Stephan Meister⁵, Grennady Wirjanata⁶, Andrea Ruecker⁴, Leanna M Upton⁴, Tara S Abraham², Mariana J Almeida², Anupam Pradhan⁷, Achim Porzelle¹, Torsten Luksch, María Santos Martínez⁸, Torsten Luksch, Judith M Bolscher⁹, Andrew Woodland¹, Suzanne Norval¹, Fabio Zuccotto¹, John Thomas¹, Frederick Simeons¹, Laste Stojanovski¹, Maria Osuna-Cabello¹, Paddy M Brock⁴, Tom S Churcher⁴, Katarzyna A Sala⁴, Sara E Zakutansky⁴, María Belén Jiménez-Díaz⁸, Laura Maria Sanz⁸, Jennifer Riley¹, Rajshekhar Basak², Michael Campbell¹⁰, Vicky M Avery¹¹, Robert W Sauerwein⁹, Koen J Dechering⁹, Rintis Noviyanti¹², Brice Campo¹³, Julie A Frearson¹, Iñigo Angulo-Barturen⁸, Santiago Ferrer-Bazaga⁸, Francisco Javier Gamo⁸, Paul G Wyatt¹, Didier Leroy¹³, Peter Siegl¹³, Michael J Delves⁴, Dennis E Kyle⁷, Sergio Wittlin¹⁴, Jutta Marfurt⁶, Ric N Price¹⁵, Robert E Sinden⁴, Elizabeth A Winzeler⁵, Susan A Charman¹⁰, Lidiya Bebrevska¹³, David W Gray¹, Simon Campbell¹³, Alan H Fairlamb¹, Paul A Willis¹³, Julian C Rayner³, David A Fidock¹⁶, Kevin D Read¹, Ian H Gilbert¹

Affiliations

¹ Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
² Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
³ Malaria Programme, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK.
⁴ Department of Life Sciences, Imperial College, London SW7 2AZ, UK.
⁵ University of California, San Diego, School of Medicine, 9500 Gilman Drive 0760, La Jolla, California 92093, USA.
⁶ Global Health and Tropical Medicine Division, Menzies School of Health Research, Charles Darwin University, PO Box 41096, Casuarina, Darwin, Northern Territory 0811, Australia.
⁷ Department of Global Health, College of Public Health University of South Florida, 3720 Spectrum Boulevard, Suite 304, Tampa, Florida 33612, USA.
⁸ GlaxoSmithKline, Tres Cantos Medicines Development Campus-Diseases of the Developing World, Severo Ochoa 2, Tres Cantos 28760, Madrid, Spain.
⁹ TropIQ Health Sciences, Geert Grooteplein 28, Huispost 268, 6525 GA Nijmegen, The Netherlands.
¹⁰ Centre for Drug Candidate Optimisation, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
¹¹ Eskitis Institute, Brisbane Innovation Park, Nathan Campus, Griffith University, Queensland 4111, Australia.
¹² Malaria Pathogenesis Laboratory, Eijkman Institute for Molecular Biology, Jalan Diponegoro 69, 10430 Jakarta, Indonesia.
¹³ Medicines for Malaria Venture, PO Box 1826, 20 route de Pre-Bois, 1215 Geneva 15, Switzerland.
¹⁴ Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051 Basel, Switzerland.
¹⁵ 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.
¹⁶ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antimalarials / administration & dosage
Antimalarials / adverse effects
Antimalarials / pharmacokinetics
Antimalarials / pharmacology*
Drug Discovery
Female
Gene Expression Regulation / drug effects*
Life Cycle Stages / drug effects
Liver / drug effects
Liver / parasitology
Malaria / drug therapy
Malaria / parasitology*
Male
Models, Molecular
Peptide Elongation Factor 2 / antagonists & inhibitors
Peptide Elongation Factor 2 / metabolism
Plasmodium / drug effects*
Plasmodium / genetics
Plasmodium / growth & development
Plasmodium / metabolism*
Plasmodium berghei / drug effects
Plasmodium berghei / physiology
Plasmodium falciparum / drug effects
Plasmodium falciparum / metabolism
Plasmodium vivax / drug effects
Plasmodium vivax / metabolism
Protein Biosynthesis / drug effects*
Quinolines / administration & dosage
Quinolines / chemistry
Quinolines / pharmacokinetics
Quinolines / pharmacology*

Substances

Antimalarials
DDD107498
Peptide Elongation Factor 2
Quinolines

Abstract

Publication types

MeSH terms

Substances

Grants and funding