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Chemical genetics of Plasmodium falciparum

Author

Listed:
  • W. Armand Guiguemde

    (St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA)

  • Anang A. Shelat

    (St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA)

  • David Bouck

    (St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA)

  • Sandra Duffy

    (Discovery Biology, Eskitis Institute for Cell and Molecular Therapies, Griffith University)

  • Gregory J. Crowther

    (University of Washington, Seattle, Washington 98195-7185, USA)

  • Paul H. Davis

    (University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA)

  • David C. Smithson

    (St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA)

  • Michele Connelly

    (St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA)

  • Julie Clark

    (St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA)

  • Fangyi Zhu

    (St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA)

  • María B. Jiménez-Díaz

    (GlaxoSmithKline, Tres Cantos Medicines Development Campus, Diseases of Developing World)

  • María S. Martinez

    (GlaxoSmithKline, Tres Cantos Medicines Development Campus, Diseases of Developing World)

  • Emily B. Wilson

    (University of California, San Francisco, California 94158-2542, USA)

  • Abhai K. Tripathi

    (Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA)

  • Jiri Gut

    (San Francisco General Hospital, University of California, San Francisco, California 94143, USA)

  • Elizabeth R. Sharlow

    (University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA)

  • Ian Bathurst

    (Medicines for Malaria Venture)

  • Farah El Mazouni

    (University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9041, USA)

  • Joseph W. Fowble

    (University of Washington, Seattle, Washington 98195-7185, USA)

  • Isaac Forquer

    (Experimental Chemotherapy Lab, Portland VA Medical Center, Portland, Oregon 97239, USA)

  • Paula L. McGinley

    (The State University of New Jersey, Piscataway, New Jersey 08854, USA)

  • Steve Castro

    (The State University of New Jersey, Piscataway, New Jersey 08854, USA)

  • Iñigo Angulo-Barturen

    (GlaxoSmithKline, Tres Cantos Medicines Development Campus, Diseases of Developing World)

  • Santiago Ferrer

    (GlaxoSmithKline, Tres Cantos Medicines Development Campus, Diseases of Developing World)

  • Philip J. Rosenthal

    (San Francisco General Hospital, University of California, San Francisco, California 94143, USA)

  • Joseph L. DeRisi

    (University of California, San Francisco, California 94158-2542, USA)

  • David J. Sullivan

    (Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA)

  • John S. Lazo

    (University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA)

  • David S. Roos

    (University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA)

  • Michael K. Riscoe

    (Experimental Chemotherapy Lab, Portland VA Medical Center, Portland, Oregon 97239, USA)

  • Margaret A. Phillips

    (University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9041, USA)

  • Pradipsinh K. Rathod

    (University of Washington, Seattle, Washington 98195-7185, USA)

  • Wesley C. Van Voorhis

    (University of Washington, Seattle, Washington 98195-7185, USA)

  • Vicky M. Avery

    (Discovery Biology, Eskitis Institute for Cell and Molecular Therapies, Griffith University)

  • R. Kiplin Guy

    (St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA)

Abstract

Malaria caused by Plasmodium falciparum is a disease that is responsible for 880,000 deaths per year worldwide. Vaccine development has proved difficult and resistance has emerged for most antimalarial drugs. To discover new antimalarial chemotypes, we have used a phenotypic forward chemical genetic approach to assay 309,474 chemicals. Here we disclose structures and biological activity of the entire library—many of which showed potent in vitro activity against drug-resistant P. falciparum strains—and detailed profiling of 172 representative candidates. A reverse chemical genetic study identified 19 new inhibitors of 4 validated drug targets and 15 novel binders among 61 malarial proteins. Phylochemogenetic profiling in several organisms revealed similarities between Toxoplasma gondii and mammalian cell lines and dissimilarities between P. falciparum and related protozoans. One exemplar compound displayed efficacy in a murine model. Our findings provide the scientific community with new starting points for malaria drug discovery.

Suggested Citation

  • W. Armand Guiguemde & Anang A. Shelat & David Bouck & Sandra Duffy & Gregory J. Crowther & Paul H. Davis & David C. Smithson & Michele Connelly & Julie Clark & Fangyi Zhu & María B. Jiménez-Díaz & Mar, 2010. "Chemical genetics of Plasmodium falciparum," Nature, Nature, vol. 465(7296), pages 311-315, May.
    • Handle: RePEc:nat:nature:v:465:y:2010:i:7296:d:10.1038_nature09099
    DOI: 10.1038/nature09099
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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.

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