A novel multiple-stage antimalarial agent that inhibits protein synthesis.

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

Journal:
Nature, Volume: 522, Issue: 7556
Published:
June 18, 2015
PMID:
26085270
Authors:
Beatriz Baragaña B, Irene Hallyburton I, Marcus C S Lee MC, Neil R Norcross NR, Raffaella Grimaldi R, Thomas D Otto TD, William R Proto WR, Andrew M Blagborough AM, Stephan Meister S, Grennady Wirjanata G, Andrea Ruecker A, Leanna M Upton LM, Tara S Abraham TS, Mariana J Almeida MJ, Anupam Pradhan A, Achim Porzelle A, Torsten Luksch , María Santos Martínez MS, Torsten Luksch T, Judith M Bolscher JM, Andrew Woodland A, Suzanne Norval S, Fabio Zuccotto F, John Thomas J, Frederick Simeons F, Laste Stojanovski L, Maria Osuna-Cabello M, Paddy M Brock PM, Tom S Churcher TS, Katarzyna A Sala KA, Sara E Zakutansky SE, María Belén Jiménez-Díaz MB, Laura Maria Sanz LM, Jennifer Riley J, Rajshekhar Basak R, Michael Campbell M, Vicky M Avery VM, Robert W Sauerwein RW, Koen J Dechering KJ, Rintis Noviyanti R, Brice Campo B, Julie A Frearson JA, Iñigo Angulo-Barturen I, Santiago Ferrer-Bazaga S, Francisco Javier Gamo FJ, Paul G Wyatt PG, Didier Leroy D, Peter Siegl P, Michael J Delves MJ, Dennis E Kyle DE, Sergio Wittlin S, Jutta Marfurt J, Ric N Price RN, Robert E Sinden RE, Elizabeth A Winzeler EA, Susan A Charman SA, Lidiya Bebrevska L, David W Gray DW, Simon Campbell S, Alan H Fairlamb AH, Paul A Willis PA, Julian C Rayner JC, David A Fidock DA, Kevin D Read KD, Ian H Gilbert IH
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.