A novel multiple-stage antimalarial agent that inhibits protein synthesis

TY - JOUR

T1 - A novel multiple-stage antimalarial agent that inhibits protein synthesis

AU - Baragana, Beatriz

AU - Hallyburton, Irene

AU - Lee, Marcus C. S.

AU - Norcross, Neil R.

AU - Grimaldi, Raffaella

AU - Otto, Thomas D.

AU - Proto, William R.

AU - Blagborough, Andrew M.

AU - Meister, Stephan

AU - Wirjanata, Grennady

AU - Ruecker, Andrea

AU - Upton, Leanna M.

AU - Abraham, Tara S.

AU - Almeida, Mariana J.

AU - Pradhan, Anupam

AU - Porzelle, Achim

AU - Santos Martinez, Maria

AU - Bolscher, Judith M.

AU - Woodland, Andrew

AU - Luksch, Torsten

AU - Norval, Suzanne

AU - Zuccotto, Fabio

AU - Thomas, John

AU - Simeons, Frederick

AU - Stojanovski, Laste

AU - Osuna-Cabello, Maria

AU - Brock, Paddy M.

AU - Churcher, Tom S.

AU - Sala, Katarzyna A.

AU - Zakutansky, Sara E.

AU - Belén Jiménez-Díaz, María

AU - Maria Sanz, Laura

AU - Riley, Jennifer

AU - Basak, Rajshekhar

AU - Campbell, Michael

AU - Avery, Vicky M.

AU - Sauerwein, Robert W.

AU - Dechering, Koen J.

AU - Noviyanti, Rintis

AU - Campo, Brice

AU - Frearson, Julie A.

AU - Angulo-Barturen, Inigo

AU - Ferrer-Bazaga, Santiago

AU - Javier Gamo, Francisco

AU - Wyatt, Paul G.

AU - Leroy, Didier

AU - Siegl, Peter

AU - Delves, Michael J.

AU - Kyle, Dennis E.

AU - Wittlin, Sergio

AU - Marfurt, Jutta

AU - Price, Ric N.

AU - Sinden, Robert E.

AU - Winzeler, Elizabeth A.

AU - Charman, Susan A.

AU - Bebrevska, Lidiya

AU - Gray, David W.

AU - Campbell, Simon

AU - Fairlamb, Alan H.

AU - Willis, Paul A.

AU - Rayner, Julian C.

AU - Fidock, David A.

AU - Read, Kevin D.

AU - Gilbert, Ian H.

N1 - Copyright: © 2015, Springer Nature Limited.

PY - 2015/6/18

Y1 - 2015/6/18

N2 - 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.

AB - 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.

KW - Drug discovery and development

KW - Malaria

KW - Target identification

U2 - 10.1038/nature14451

DO - 10.1038/nature14451

M3 - Article

C2 - 26085270

SN - 0028-0836

VL - 522

SP - 315

EP - 320

JO - Nature

JF - Nature

IS - 7556

ER -