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 ForquerPaula 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, R. Kiplin Guy

Research output: Contribution to journalArticlepeer-review

487 Scopus citations

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 libraryĝ€"many of which showed potent in vitro activity against drug-resistant P. falciparum strainsĝ€" 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.

Original languageEnglish
Pages (from-to)311-315
Number of pages5
JournalNature
Volume465
Issue number7296
DOIs
StatePublished - May 20 2010

Bibliographical note

Funding Information:
Acknowledgements This work was supported by the American Lebanese Syrian Associated Charities (ALSAC) and St Jude Children’s Research Hospital (SJCRH, R.K.G.), the Medicines for Malaria Venture (W.C.V.V. and V.M.A.), National Institute of Allergy and Infectious Diseases (AI772682 (P.H.D.), AI075517 (R.K.G.), AI067921 (W.C.V.V.) and AI080625 (W.C.V.V.), AI28724 (D.S.R.), AI53862 (J.L.D.), AI35707 (P.J.R.), AI053680 (M.A.P. and P.K.R.), AI075594 (M.A.P., P.K.R. and I.B.), AI082617 (P.K.R.) and AI045774 (D.J.S.)), the National Cancer Institute (CA78039 (J.S.L.)), the Welch Foundation (I-1257 (M.A.P.)), the Doris Duke Charitable Foundation (P.J.R.), and the Ellison Medical Foundation (D.S.R.). We acknowledge A. B. Vaidya for providing the parasite strain D10_yDHOD. We acknowledge M. Sigal for assistance in the early leads project coordination, the SJCRH High Throughput Screening Center, particularly J. Cui; the SJCRH Lead Discovery Informatics Center, and the SJCRH High Throughput Analytical Chemistry Center, particularly C. Nelson and A. Lemoff; at UW, F. Buckner, W. Hol and A. Napuli (AI067921, W. Hol); S. Wei and W. Hao in the UT Southwestern HTS Center; and the Australian Red Cross Blood Service for the provision of O1 erythrocytes to Griffith University.

ASJC Scopus subject areas

  • General

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