Chemical genetics of Plasmodium falciparum

Guiguemde, W. Armand; Shelat, Anang A.; Bouck, David; Duffy, Sandra; Crowther, Gregory J.; Davis, Paul H.; Smithson, David C; Connelly, Michele; Clark, Julie; Zhu, Fangyi; Jiménez-Díaz, María B; Escolano-Martínez, María S; Wilson, Emily B.; Tripathi, Abhai K.; Gut, Jiri; Sharlow, Elizabeth R.; Bathurst, Ian; El Mazouni, Farah; Fowble, Joseph W; Forquer, Isaac; McGinley, Paula L; Castro, Steve; Angulo-Barturen, Iñigo; Estaún Ferrer, Santiago; Rosenthal, Philip J.; DeRisi, Joseph L.; Sullivan, David J.; Lazo, John S.; Roos, David S.; Riscoe, Michael K.; Phillips, Margaret A.; Rathod, Pradipsinh K.; Van Voorhis, Wesley C.; Avery, Vicky M; Guy, R. Kiplin

doi:10.1038/nature09099

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Chemical genetics of Plasmodium falciparum

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Author(s): W. Armand Guiguemde ¹ , Anang A. Shelat ¹ , David Bouck ¹ , Sandra Duffy ² , Gregory J. Crowther ³ , Paul H. Davis ⁴ , David C. Smithson ¹ , Michele Connelly ¹ , Julie Clark ¹ , Fangyi Zhu ¹ , María B Jiménez-Díaz ⁵ , María S Martinez ⁵ , Emily B. Wilson ⁶ , Abhai K. Tripathi ⁷ , Jiri Gut ⁸ , Elizabeth R. Sharlow ⁹ , Ian Bathurst ¹⁰ , Farah El Mazouni ¹¹ , Joseph W Fowble ¹² , Isaac Forquer ¹³ , Paula L McGinley ¹⁴ , Steve Castro ¹⁴ , Iñigo Angulo-Barturen ⁵ , Santiago Ferrer ⁵ , Philip J. Rosenthal ⁸ , Joseph L DeRisi ⁶ , David J. Sullivan Jr ⁷ , John S. Lazo ⁹ , David S. Roos ⁴ , Michael K. Riscoe ¹³ , Margaret A. Phillips ¹¹ , Pradipsinh K. Rathod ¹² , Wesley C. Van Voorhis ³ , Vicky M Avery ² , R. Kiplin Guy ¹

Publication date PMC-release: 20 November 2010

Journal: Nature

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Abstract

Malaria caused by Plasmodium falciparum is a catastrophic disease worldwide (880,000 deaths yearly). Vaccine development has proved difficult and resistance has emerged for most antimalarials. In order to discover new antimalarial chemotypes, we have employed 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 exhibited potent in vitro activity against drug resistant 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 multiple 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. Overall, our findings provide the scientific community with new starting points for malaria drug discovery.

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Artemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease. There are recent concerns that the efficacy of such therapies has declined on the Thai-Cambodian border, historically a site of emerging antimalarial-drug resistance. In two open-label, randomized trials, we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin, western Cambodia, and Wang Pha, northwestern Thailand: oral artesunate given at a dose of 2 mg per kilogram of body weight per day, for 7 days, and artesunate given at a dose of 4 mg per kilogram per day, for 3 days, followed by mefloquine at two doses totaling 25 mg per kilogram. We assessed in vitro and in vivo Plasmodium falciparum susceptibility, artesunate pharmacokinetics, and molecular markers of resistance. We studied 40 patients in each of the two locations. The overall median parasite clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours (interquartile range, 36 to 66) in Wang Pha (P<0.001). Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients (30%) receiving artesunate monotherapy and 1 of 20 (5%) receiving artesunate-mefloquine therapy in Pailin, as compared with 2 of 20 (10%) and 1 of 20 (5%), respectively, in Wang Pha (P=0.31). These markedly different parasitologic responses were not explained by differences in age, artesunate or dihydroartemisinin pharmacokinetics, results of isotopic in vitro sensitivity tests, or putative molecular correlates of P. falciparum drug resistance (mutations or amplifications of the gene encoding a multidrug resistance protein [PfMDR1] or mutations in the gene encoding sarco-endoplasmic reticulum calcium ATPase6 [PfSERCA]). Adverse events were mild and did not differ significantly between the two treatment groups. P. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand. Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing. Containment measures are urgently needed. (ClinicalTrials.gov number, NCT00493363, and Current Controlled Trials number, ISRCTN64835265.) 2009 Massachusetts Medical Society

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Author and article information

Journal

Journal ID (nlm-journal-id): 0410462

Journal ID (pubmed-jr-id): 6011

Journal ID (nlm-ta): Nature

Title: Nature

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date Nihms-submitted: 3 May 2010

Publication date (Print): 20 May 2010

Publication date PMC-release: 20 November 2010

Volume: 465

Issue: 7296

Pages: 311-315

Affiliations

[1 ]Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

[2 ]Discovery Biology, Eskitis Institute for Cell and Molecular Therapies, Griffith University, Brisbane, AUSTRALIA

[3 ]Department of Medicine, University of Washington, Seattle, Washington 98195-7185, USA

[4 ]Department of Biology and the Penn Genome Frontiers Institute, University of Pennsylvania,Philadelphia, Pennsylvania 19104, USA

[5 ]GlaxoSmithKline, Tres Cantos Medicines Development Campus, Diseases of Developing World, Tres Cantos, Madrid, Spain

[6 ]Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158-2542, USA

[7 ]W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA

[8 ]Department of Medicine, San Francisco General Hospital, University of California, San Francisco, CA 94143, USA

[9 ]Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261 USA

[10 ]Medicines for Malaria Venture, Geneva, SWITZERLAND

[11 ]Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9041, USA

[12 ]Department of Chemistry, University of Washington, Seattle, Washington 98195-7185, USA

[13 ]Experimental Chemotherapy Lab, Portland VA Medical Center, Portland, Oregon 97239

[14 ]Department of Chemistry and Chemical Biology Rutgers, The State University of New Jersey,Piscataway, New Jersey 08854

Author notes

Correspondence and requests for materials should be addressed to: R. Kiplin Guy. Phone: (901)595-5714. Fax: (901) 595-5715. kip.guy@ 123456stjude.org .

Author contributions

WAG and RKG designed and coordinated the project. AAS wrote the algorithms for the data analysis and generated the figures. Assays were conceived, performed and analyzed by WAG and DB ( P. falciparum phenotypic screen), MC (human cell lines), DCS ( T. brucei), PHD and DSR ( T. gondii), JSL and ERS ( L. major), AKT and DJS (hemozoin inhibition), GJC and WCVV (thermal melt experiments) MAP, PKR and FEM (PfDHOD), JWF and PKR ( P. falciparum dihydrofolate reductase), JG and PJR (FP-2), IF and MKR (cytochrome bc 1), JC ( P.falciparum mutant drug sensitivity). EBW, SD, JLD and VMA (independent antimalarial in vitro experiments), FZ ( in vitro pharmacokinetics), MBJD, MSM, IAB and SF ( in vivo pharmacokinetics and efficacy), IB (coordination of technology development and network development), SC and PLM (resynthesis). WAG, AAS and RKG wrote the manuscript. All authors contributed to the design of the experiments.and the preparation of the manuscript.

Article

Manuscript ID: nihpa198454

DOI: 10.1038/nature09099

PMC ID: 2874979

PubMed ID: 20485428

SO-VID: 3f0904ad-5eb0-43c2-ae72-223e2206978b

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