A novel multiple-stage antimalarial agent that inhibits protein synthesis

Beatriz Baragana; 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; Maria Santos Martinez; Judith M. Bolscher; Andrew Woodland; Torsten Luksch; 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; Inigo 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

Beatriz Baragana, 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, Maria Santos Martinez, Judith M. Bolscher, Andrew Woodland, Torsten LukschSuzanne 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, Inigo 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

Research output: Contribution to journal › Article › peer-review

188 Citations (Scopus)

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.

Original language	English
Pages (from-to)	315-320
Number of pages	6
Journal	Nature
Volume	522
Issue number	7556
DOIs	https://doi.org/10.1038/nature14451
Publication status	Published - 18 Jun 2015

Access to Document

10.1038/nature14451

2 Finished

A Translational Engine for Biomedical Discoveries (Strategic Grant)
Fairlamb, A. & Gilbert, I.
Wellcome Trust
1/01/13 → 30/09/15
Project: Research
Aref#d: 18185. Characterization and validation of drug targets in the Kinetoplastida (Principal Research Fellowship/Programme Grant)
Fairlamb, A.
Wellcome Trust
1/10/06 → 30/09/17
Project: Research

188 Citations
1 Article

Corrigendum: A novel multiple-stage antimalarial agent that inhibits protein synthesis
Baragaña, B., Hallyburton, I., Lee, M. C. S., Norcross, N. R., Grimaldi, R., Otto, T. D., Proto, W. R., Blagborough, A. M., Meister, S., Wirjanata, G., Ruecker, A., Upton, L. M., Abraham, T. S., Almeida, M. J., Pradhan, A., Porzelle, A., Santos Martinez, M., Bolscher, J. M., Woodland, A., Luksch, T. & 44 others, Norval, S., Zuccotto, F., Thomas, J., Simeons, F., Stojanovski, L., Osuna-Cabello, M., Brock, P. M., Churcher, T. S., Sala, K. A., Zakutansky, S. E., Jiménez-Díaz, M. B., Sanz, L. M., Riley, J., Basak, R., Campbell, M., Avery, V. M., Sauerwein, R. W., Dechering, K. J., Noviyanti, R., Campo, B., Frearson, J. A., Angulo-Barturen, I., Ferrer-Bazaga, S., Javier Gamo, F., Wyatt, P. G., Leroy, D., Siegl, P., Delves, M. J., Kyle, D. E., Wittlin, S., Marfurt, J., Price, R. N., Sinden, R. E., Winzeler, E. A., Charman, S. A., Bebrevska, L., Gray, D. W., Campbell, S., Fairlamb, A. H., Willis, P. A., Rayner, J. C., Fidock, D. A., Read, K. D. & Gilbert, I. H., 25 May 2016, In: Nature. 537, 7618, p. 122 1 p.
Research output: Contribution to journal › Article › peer-review
2 Citations (Scopus)

Gilbert, Ian
- Biological Chemistry and Drug Discovery - Professor
Person: Academic
Read, Kevin
- Drug Discovery Unit - Professor & Personal Chair of Quantitative Pharmacology
Person: Academic

Cite this

Baragana, B., Hallyburton, I., Lee, M. C. S., Norcross, N. R., Grimaldi, R., Otto, T. D., Proto, W. R., Blagborough, A. M., Meister, S., Wirjanata, G., Ruecker, A., Upton, L. M., Abraham, T. S., Almeida, M. J., Pradhan, A., Porzelle, A., Santos Martinez, M., Bolscher, J. M., Woodland, A., ... Gilbert, I. H. (2015). A novel multiple-stage antimalarial agent that inhibits protein synthesis. Nature, 522(7556), 315-320. https://doi.org/10.1038/nature14451

Baragana, Beatriz ; Hallyburton, Irene ; Lee, Marcus C. S. ; Norcross, Neil R. ; Grimaldi, Raffaella ; Otto, Thomas D. ; Proto, William R. ; Blagborough, Andrew M. ; Meister, Stephan ; Wirjanata, Grennady ; Ruecker, Andrea ; Upton, Leanna M. ; Abraham, Tara S. ; Almeida, Mariana J. ; Pradhan, Anupam ; Porzelle, Achim ; Santos Martinez, Maria ; Bolscher, Judith M. ; Woodland, Andrew ; Luksch, Torsten ; Norval, Suzanne ; Zuccotto, Fabio ; Thomas, John ; Simeons, Frederick ; Stojanovski, Laste ; Osuna-Cabello, Maria ; Brock, Paddy M. ; Churcher, Tom S. ; Sala, Katarzyna A. ; Zakutansky, Sara E. ; Belén Jiménez-Díaz, María ; Maria Sanz, Laura ; Riley, Jennifer ; Basak, Rajshekhar ; Campbell, Michael ; Avery, Vicky M. ; Sauerwein, Robert W. ; Dechering, Koen J. ; Noviyanti, Rintis ; Campo, Brice ; Frearson, Julie A. ; Angulo-Barturen, Inigo ; Ferrer-Bazaga, Santiago ; Javier Gamo, Francisco ; Wyatt, Paul G. ; Leroy, Didier ; Siegl, Peter ; Delves, Michael J. ; Kyle, Dennis E. ; Wittlin, Sergio ; Marfurt, Jutta ; Price, Ric N. ; Sinden, Robert E. ; Winzeler, Elizabeth A. ; Charman, Susan A. ; Bebrevska, Lidiya ; Gray, David W. ; Campbell, Simon ; Fairlamb, Alan H. ; Willis, Paul A. ; Rayner, Julian C. ; Fidock, David A. ; Read, Kevin D. ; Gilbert, Ian H. / A novel multiple-stage antimalarial agent that inhibits protein synthesis. In: Nature. 2015 ; Vol. 522, No. 7556. pp. 315-320.

@article{fa5a48e05810478ca534e12b2ab08884,

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.",

author = "Beatriz Baragana and Irene Hallyburton and Lee, {Marcus C. S.} and Norcross, {Neil R.} and Raffaella Grimaldi and Otto, {Thomas D.} and Proto, {William R.} and Blagborough, {Andrew M.} and Stephan Meister and Grennady Wirjanata and Andrea Ruecker and Upton, {Leanna M.} and Abraham, {Tara S.} and Almeida, {Mariana J.} and Anupam Pradhan and Achim Porzelle and {Santos Martinez}, Maria and Bolscher, {Judith M.} and Andrew Woodland and Torsten Luksch and Suzanne Norval and Fabio Zuccotto and John Thomas and Frederick Simeons and Laste Stojanovski and Maria Osuna-Cabello and Brock, {Paddy M.} and Churcher, {Tom S.} and Sala, {Katarzyna A.} and Zakutansky, {Sara E.} and {Bel{\'e}n Jim{\'e}nez-D{\'i}az}, Mar{\'i}a and {Maria Sanz}, Laura and Jennifer Riley and Rajshekhar Basak and Michael Campbell and Avery, {Vicky M.} and Sauerwein, {Robert W.} and Dechering, {Koen J.} and Rintis Noviyanti and Brice Campo and Frearson, {Julie A.} and Inigo Angulo-Barturen and Santiago Ferrer-Bazaga and {Javier Gamo}, Francisco and Wyatt, {Paul G.} and Didier Leroy and Peter Siegl and Delves, {Michael J.} and Kyle, {Dennis E.} and Sergio Wittlin and Jutta Marfurt and Price, {Ric N.} and Sinden, {Robert E.} and Winzeler, {Elizabeth A.} and Charman, {Susan A.} and Lidiya Bebrevska and Gray, {David W.} and Simon Campbell and Fairlamb, {Alan H.} and Willis, {Paul A.} and Rayner, {Julian C.} and Fidock, {David A.} and Read, {Kevin D.} and Gilbert, {Ian H.}",

year = "2015",

month = jun,

day = "18",

doi = "10.1038/nature14451",

language = "English",

volume = "522",

pages = "315--320",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7556",

}

Baragana, B, Hallyburton, I, Lee, MCS, Norcross, NR, Grimaldi, R, Otto, TD, Proto, WR, Blagborough, AM, Meister, S, Wirjanata, G, Ruecker, A, Upton, LM, Abraham, TS, Almeida, MJ, Pradhan, A, Porzelle, A, Santos Martinez, M, Bolscher, JM, Woodland, A, Luksch, T, Norval, S, Zuccotto, F, Thomas, J, Simeons, F, Stojanovski, L , Osuna-Cabello, M, Brock, PM, Churcher, TS, Sala, KA, Zakutansky, SE, Belén Jiménez-Díaz, M, Maria Sanz, L, Riley, J, Basak, R, Campbell, M, Avery, VM, Sauerwein, RW, Dechering, KJ, Noviyanti, R, Campo, B, Frearson, JA, Angulo-Barturen, I, Ferrer-Bazaga, S, Javier Gamo, F, Wyatt, PG, Leroy, D, Siegl, P, Delves, MJ, Kyle, DE, Wittlin, S, Marfurt, J, Price, RN, Sinden, RE, Winzeler, EA, Charman, SA, Bebrevska, L, Gray, DW, Campbell, S, Fairlamb, AH, Willis, PA, Rayner, JC, Fidock, DA, Read, KD & Gilbert, IH 2015, 'A novel multiple-stage antimalarial agent that inhibits protein synthesis', Nature, vol. 522, no. 7556, pp. 315-320. https://doi.org/10.1038/nature14451

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

In: Nature, Vol. 522, No. 7556, 18.06.2015, p. 315-320.

Research output: Contribution to journal › Article › peer-review

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.

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.

U2 - 10.1038/nature14451

DO - 10.1038/nature14451

M3 - Article

C2 - 26085270

VL - 522

SP - 315

EP - 320

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7556

ER -

A novel multiple-stage antimalarial agent that inhibits protein synthesis

Abstract

Access to Document

A Translational Engine for Biomedical Discoveries (Strategic Grant)

Aref#d: 18185. Characterization and validation of drug targets in the Kinetoplastida (Principal Research Fellowship/Programme Grant)

Corrigendum: A novel multiple-stage antimalarial agent that inhibits protein synthesis

Gilbert, Ian

Read, Kevin

Cite this