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Thousands of chemical starting points for antimalarial lead identification

Author

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  • Francisco-Javier Gamo

    (Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain)

  • Laura M. Sanz

    (Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain)

  • Jaume Vidal

    (Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain)

  • Cristina de Cozar

    (Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain)

  • Emilio Alvarez

    (Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain)

  • Jose-Luis Lavandera

    (Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain)

  • Dana E. Vanderwall

    (Computational and Structural Chemistry, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, North Carolina 27709-3398, USA)

  • Darren V. S. Green

    (Computational and Structural Chemistry, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Hertfordshire, Stevenage SG1 2NY, UK)

  • Vinod Kumar

    (Computational Biology, Quantitative Sciences, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA)

  • Samiul Hasan

    (Computational Biology, Quantitative Sciences, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA)

  • James R. Brown

    (Computational Biology, Quantitative Sciences, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA)

  • Catherine E. Peishoff

    (Computational and Structural Chemistry, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA)

  • Lon R. Cardon

    (Quantitative Sciences, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, USA)

  • Jose F. Garcia-Bustos

    (Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain)

Abstract

Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chemical class of antimalarials has been introduced into clinical practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compounds in GlaxoSmithKline’s chemical library for inhibitors of P. falciparum, of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 µM concentration. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compounds originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host–pathogen interaction related targets. Chemical structures and associated data are hereby made public to encourage additional drug lead identification efforts and further research into this disease.

Suggested Citation

  • Francisco-Javier Gamo & Laura M. Sanz & Jaume Vidal & Cristina de Cozar & Emilio Alvarez & Jose-Luis Lavandera & Dana E. Vanderwall & Darren V. S. Green & Vinod Kumar & Samiul Hasan & James R. Brown &, 2010. "Thousands of chemical starting points for antimalarial lead identification," Nature, Nature, vol. 465(7296), pages 305-310, May.
    • Handle: RePEc:nat:nature:v:465:y:2010:i:7296:d:10.1038_nature09107
    DOI: 10.1038/nature09107
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    Cited by:

    1. Deyun Qiu & Jinxin V. Pei & James E. O. Rosling & Vandana Thathy & Dongdi Li & Yi Xue & John D. Tanner & Jocelyn Sietsma Penington & Yi Tong Vincent Aw & Jessica Yi Han Aw & Guoyue Xu & Abhai K. Tripa, 2022. "A G358S mutation in the Plasmodium falciparum Na+ pump PfATP4 confers clinically-relevant resistance to cipargamin," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Selina Bopp & Charisse Flerida A. Pasaje & Robert L. Summers & Pamela Magistrado-Coxen & Kyra A. Schindler & Victoriano Corpas-Lopez & Tomas Yeo & Sachel Mok & Sumanta Dey & Sebastian Smick & Armiyaw , 2023. "Potent acyl-CoA synthetase 10 inhibitors kill Plasmodium falciparum by disrupting triglyceride formation," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Stanley C. Xie & Yinuo Wang & Craig J. Morton & Riley D. Metcalfe & Con Dogovski & Charisse Flerida A. Pasaje & Elyse Dunn & Madeline R. Luth & Krittikorn Kumpornsin & Eva S. Istvan & Joon Sung Park &, 2024. "Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    4. Krittikorn Kümpornsin & Theerarat Kochakarn & Tomas Yeo & John Okombo & Madeline R. Luth & Johanna Hoshizaki & Mukul Rawat & Richard D. Pearson & Kyra A. Schindler & Sachel Mok & Heekuk Park & Anne-Ca, 2023. "Generation of a mutator parasite to drive resistome discovery in Plasmodium falciparum," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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