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 Sosa Abraham, Mariana Justino de Almeida, Anupam Pradhan, Achim Porzelle, Maria Santos Martinez, Judith M Bolscher, Andrew Woodland, Suzanne Norval & 30 others Fabio Zuccotto, John Thomas, Frederick Simeons, Laste Stojanovski, Maria Osuna-Cabello, Paddy M Brock, Thomas S Churcher, Katarzyna A Sala, Sara E Zakutansky, Maria Belen Jimenez-Diaz, Laura M 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, Susan A Charman

Research output: Contribution to journalArticleResearchpeer-review

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 languageEnglish
Pages (from-to)315-320
Number of pages6
JournalNature
Volume522
Issue number7556
DOIs
Publication statusPublished - 2015

Cite this

Baragana, B., Hallyburton, I., Lee, M. C. S., Norcross, N. R., Grimaldi, R., Otto, T. D., ... Charman, S. A. (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 Sosa ; Justino de Almeida, Mariana ; Pradhan, Anupam ; Porzelle, Achim ; Martinez, Maria Santos ; Bolscher, Judith M ; Woodland, Andrew ; Norval, Suzanne ; Zuccotto, Fabio ; Thomas, John ; Simeons, Frederick ; Stojanovski, Laste ; Osuna-Cabello, Maria ; Brock, Paddy M ; Churcher, Thomas S ; Sala, Katarzyna A ; Zakutansky, Sara E ; Jimenez-Diaz, Maria Belen ; Sanz, Laura M ; 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 ; Gamo, Francisco-Javier ; Wyatt, Paul G ; Leroy, Didier ; Siegl, Peter ; Delves, Michael J ; Kyle, Dennis E ; Wittlin, Sergio ; Charman, Susan A. / A novel multiple-stage antimalarial agent that inhibits protein synthesis. In: Nature. 2015 ; Vol. 522, No. 7556. pp. 315-320.
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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.",
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 Sosa} and {Justino de Almeida}, Mariana and Anupam Pradhan and Achim Porzelle and Martinez, {Maria Santos} and Bolscher, {Judith M} and Andrew Woodland 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, {Thomas S} and Sala, {Katarzyna A} and Zakutansky, {Sara E} and Jimenez-Diaz, {Maria Belen} and Sanz, {Laura M} 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 Francisco-Javier Gamo and Wyatt, {Paul G} and Didier Leroy and Peter Siegl and Delves, {Michael J} and Kyle, {Dennis E} and Sergio Wittlin and Charman, {Susan A}",
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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, Justino de Almeida, M, Pradhan, A, Porzelle, A, Martinez, MS, Bolscher, JM, Woodland, A, Norval, S, Zuccotto, F, Thomas, J, Simeons, F, Stojanovski, L, Osuna-Cabello, M, Brock, PM, Churcher, TS, Sala, KA, Zakutansky, SE, Jimenez-Diaz, MB, Sanz, LM, Riley, J, Basak, R, Campbell, M, Avery, VM, Sauerwein, RW, Dechering, KJ, Noviyanti, R, Campo, B, Frearson, JA, Angulo-Barturen, I, Ferrer-Bazaga, S, Gamo, F-J, Wyatt, PG, Leroy, D, Siegl, P, Delves, MJ, Kyle, DE, Wittlin, S & Charman, SA 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 Sosa; Justino de Almeida, Mariana; Pradhan, Anupam; Porzelle, Achim; Martinez, Maria Santos; Bolscher, Judith M; Woodland, Andrew; Norval, Suzanne; Zuccotto, Fabio; Thomas, John; Simeons, Frederick; Stojanovski, Laste; Osuna-Cabello, Maria; Brock, Paddy M; Churcher, Thomas S; Sala, Katarzyna A; Zakutansky, Sara E; Jimenez-Diaz, Maria Belen; Sanz, Laura M; 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; Gamo, Francisco-Javier; Wyatt, Paul G; Leroy, Didier; Siegl, Peter; Delves, Michael J; Kyle, Dennis E; Wittlin, Sergio; Charman, Susan A.

In: Nature, Vol. 522, No. 7556, 2015, p. 315-320.

Research output: Contribution to journalArticleResearchpeer-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 Sosa

AU - Justino de Almeida, Mariana

AU - Pradhan, Anupam

AU - Porzelle, Achim

AU - Martinez, Maria Santos

AU - Bolscher, Judith M

AU - Woodland, Andrew

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, Thomas S

AU - Sala, Katarzyna A

AU - Zakutansky, Sara E

AU - Jimenez-Diaz, Maria Belen

AU - Sanz, Laura M

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 - Gamo, Francisco-Javier

AU - Wyatt, Paul G

AU - Leroy, Didier

AU - Siegl, Peter

AU - Delves, Michael J

AU - Kyle, Dennis E

AU - Wittlin, Sergio

AU - Charman, Susan A

PY - 2015

Y1 - 2015

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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.

UR - http://www.nature.com.ezproxy.lib.monash.edu.au/nature/journal/v522/n7556/pdf/nature14451.pdf

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Baragana B, Hallyburton I, Lee MCS, Norcross NR, Grimaldi R, Otto TD et al. A novel multiple-stage antimalarial agent that inhibits protein synthesis. Nature. 2015;522(7556):315-320. https://doi.org/10.1038/nature14451