A novel multiple-stage antimalarial agent that inhibits protein synthesis

Baragaña, Beatriz and Hallyburton, Irene and Lee, Marcus C. S. and Norcross, Neil R. and Grimaldi, Raffaella and Otto, Thomas D. and Proto, William R. and Blagborough, Andrew M. and Meister, Stephan and Wirjanata, Grennady and Ruecker, Andrea and Upton, Leanna M. and Abraham, Tara S. and Almeida, Mariana J. and Pradhan, Anupam and Porzelle, Achim and Martínez, María Santos and Bolscher, Judith M. and Woodland, Andrew and Norval, Suzanne and Zuccotto, Fabio and Thomas, John and Simeons, Frederick and Stojanovski, Laste and Osuna-Cabello, Maria and Brock, Paddy M. and Churcher, Tom S. and Sala, Katarzyna A. and Zakutansky, Sara E. and Jiménez-Díaz, María Belén and Sanz, Laura Maria and Riley, Jennifer and Basak, Rajshekhar and Campbell, Michael and Avery, Vicky M. and Sauerwein, Robert W. and Dechering, Koen J. and Noviyanti, Rintis and Campo, Brice and Frearson, Julie A. and Angulo-Barturen, Iñigo and Ferrer-Bazaga, Santiago and Gamo, Francisco Javier and Wyatt, Paul G. and Leroy, Didier and Siegl, Peter and Delves, Michael J. and Kyle, Dennis E. and Wittlin, Sergio and Marfurt, Jutta and Price, Ric N. and Sinden, Robert E. and Winzeler, Elizabeth A. and Charman, Susan A. and Bebrevska, Lidiya and Gray, David W. and Campbell, Simon and Fairlamb, Alan H. and Willis, Paul A. and Rayner, Julian C. and Fidock, David A. and Read, Kevin D. and Gilbert, Ian H.. (2015) A novel multiple-stage antimalarial agent that inhibits protein synthesis. Nature, Vol. 522, H. 7556. pp. 315-320.

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Official URL: http://edoc.unibas.ch/dok/A6411079

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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.

Faculties and Departments:	09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) 09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:	Wittlin, Sergio
Item Type:	Article, refereed
Article Subtype:	Research Article
Publisher:	Macmillan
ISSN:	0028-0836
Note:	Publication type according to Uni Basel Research Database: Journal article
Related URLs:	Document Document
Identification Number:	pmid: 26085270 doi: 10.1038/nature14451
Last Modified:	04 Sep 2015 14:30
Deposited On:	04 Sep 2015 14:30

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