Chemical genetics of Plasmodium falciparum

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, María S. Martinez, Emily B. Wilson, Abhai K. Tripathi, Jiri Gut, Elizabeth R. Sharlow, Ian Bathurst, Farah El Mazouni, Joseph W. Fowble, Isaac Forquer, Paula L. McGinley, Steve Castro, Iñigo Angulo-Barturen, Santiago Ferrer, Philip J. Rosenthal, Joseph L. DeRisi, David J. Sullivan, John S. Lazo, David S. Roos, Michael K. Riscoe, Margaret A. Phillips, Pradipsinh K. Rathod, Wesley C. Van Voorhis, Vicky M. Avery and R. Kiplin Guy ()
Additional contact information
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

Nature, 2010, vol. 465, issue 7296, 311-315

Abstract: 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.

Date: 2010
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DOI: 10.1038/nature09099

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