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 journalArticle

    157 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 languageEnglish
    Pages (from-to)315-320
    Number of pages6
    JournalNature
    Volume522
    Issue number7556
    DOIs
    Publication statusPublished - 18 Jun 2015

    Cite this

    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.
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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 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.}",
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    pages = "315--320",
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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, 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 journalArticle

    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

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    SP - 315

    EP - 320

    JO - Nature

    JF - Nature

    SN - 0028-0836

    IS - 7556

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