@article{bbb3e91e96a04ae1a66a360498bf799f,
title = "Chemical genetics of Plasmodium falciparum",
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.",
author = "Guiguemde, {W. Armand} and Shelat, {Anang A.} and David Bouck and Sandra Duffy and Crowther, {Gregory J.} and Davis, {Paul H.} and Smithson, {David C.} and Michele Connelly and Julie Clark and Fangyi Zhu and Jim{\'e}nez-D{\'i}az, {Mar{\'i}a B.} and Martinez, {Mar{\'i}a S.} and Wilson, {Emily B.} and Tripathi, {Abhai K.} and Jiri Gut and Sharlow, {Elizabeth R.} and Ian Bathurst and Mazouni, {Farah El} and Fowble, {Joseph W.} and Isaac Forquer and McGinley, {Paula L.} and Steve Castro and I{\~n}igo Angulo-Barturen and Santiago Ferrer and Rosenthal, {Philip J.} and Derisi, {Joseph L.} and Sullivan, {David J.} and Lazo, {John S.} and Roos, {David S.} and Riscoe, {Michael K.} and Phillips, {Margaret A.} and Rathod, {Pradipsinh K.} and {Van Voorhis}, {Wesley C.} and Avery, {Vicky M.} and Guy, {R. Kiplin}",
note = "Funding Information: Acknowledgements This work was supported by the American Lebanese Syrian Associated Charities (ALSAC) and St Jude Children{\textquoteright}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.",
year = "2010",
month = may,
day = "20",
doi = "10.1038/nature09099",
language = "English (US)",
volume = "465",
pages = "311--315",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Research",
number = "7296",
}