Chemical genetics of Plasmodium falciparum

被引：446

作者：

Guiguemde, W. Armand ^{[1
]}

Shelat, Anang A. ^{[1
]}

Bouck, David ^{[1
]}

Duffy, Sandra ^{[2
]}

Crowther, Gregory J. ^{[3
]}

Davis, Paul H. ^{[4
,5
]}

Smithson, David C. ^{[1
]}

Connelly, Michele ^{[1
]}

Clark, Julie ^{[1
]}

Zhu, Fangyi ^{[1
]}

Jimenez-Diaz, Maria B. ^{[6
]}

Martinez, Maria S. ^{[6
]}

Wilson, Emily B. ^{[7
]}

Tripathi, Abhai K. ^{[8
]}

Gut, Jiri ^{[9
]}

Sharlow, Elizabeth R. ^{[10
]}

Bathurst, Ian ^{[11
]}

El Mazouni, Farah ^{[12
]}

Fowble, Joseph W. ^{[13
]}

Forquer, Isaac ^{[14
]}

McGinley, Paula L. ^{[15
]}

Castro, Steve ^{[15
]}

Angulo-Barturen, Inigo ^{[6
]}

Ferrer, Santiago ^{[6
]}

Rosenthal, Philip J. ^{[9
]}

DeRisi, Joseph L. ^{[7
]}

Sullivan, David J., Jr. ^{[8
]}

Lazo, John S. ^{[10
]}

Roos, David S. ^{[4
,5
]}

Riscoe, Michael K. ^{[14
]}

Phillips, Margaret A. ^{[12
]}

Rathod, Pradipsinh K. ^{[13
]}

Van Voorhis, Wesley C. ^{[3
]}

Avery, Vicky M. ^{[2
]}

Guy, R. Kiplin ^{[1
]}

机构：

[1] St Jude Childrens Res Hosp, Dept Chem Biol & Therapeut, Memphis, TN 38105 USA

[2] Griffith Univ, Eskitis Inst Cell & Mol Therapies, Brisbane, Qld 4111, Australia

[3] Univ Washington, Dept Med, Seattle, WA 98195 USA

[4] Univ Penn, Penn Genome Frontiers Inst, Philadelphia, PA 19104 USA

[5] Univ Penn, Dept Biol, Philadelphia, PA 19104 USA

[6] GlaxoSmithKline, Dis Developing World, Tres Cantos 28760, Spain

[7] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA

[8] Johns Hopkins Bloomberg Sch Publ Hlth, W Harry Feinstone Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA

[9] Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, San Francisco, CA 94143 USA

[10] Univ Pittsburgh, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15261 USA

[11] Med Malaria Venture, CH-1215 Geneva, Switzerland

[12] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA

[13] Univ Washington, Dept Chem, Seattle, WA 98195 USA

[14] Portland VA Med Ctr, Expt Chemotherapy Lab, Portland, OR 97239 USA

[15] Rutgers State Univ, Dept Chem & Chem Biol, Piscataway, NJ 08854 USA

来源：

NATURE | 2010年 / 465卷 / 7296期

关键词：

MALARIA; IDENTIFICATION; DISRUPTION; RESISTANCE; SURVIVAL; GROWTH;

D O I：

10.1038/nature09099

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：311 / 315

页数：5

共 27 条

[1] High-throughput Plasmodium falciparum growth assay for malaria drug discovery [J].

Baniecki, Mary Lynn ;

Wirth, Dyann F. ;

Clardy, Jon .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2007, 51 (02) :716-723

[2]

Cibulskis RE, 2007, AM J TROP MED HYG, V77, P133

[3] Buffer Optimization of Thermal Melt Assays of Plasmodium Proteins for Detection of Small-Molecule Ligands [J].

Crowther, Gregory J. ;

Napuli, Alberto J. ;

Thomas, Andrew P. ;

Chung, Diana J. ;

Kovzun, Kuzma V. ;

Leibly, David J. ;

Castaneda, Lisa J. ;

Bhandari, Janhavi ;

Damman, Christopher J. ;

Hui, Raymond ;

Hol, Wim G. J. ;

Buckner, Frederick S. ;

Verlinde, Christophe L. M. J. ;

Zhang, Zhongsheng ;

Fan, Erkang ;

Van Voorhis, Wesley C. .

JOURNAL OF BIOMOLECULAR SCREENING, 2009, 14 (06) :700-707

[4] Artemisinin Resistance in Plasmodium falciparum Malaria. [J].

Dondorp, Arjen M. ;

Nosten, Francois ;

Yi, Poravuth ;

Das, Debashish ;

Phyo, Aung Phae ;

Tarning, Joel ;

Lwin, Khin Maung ;

Ariey, Frederic ;

Hanpithakpong, Warunee ;

Lee, Sue J. ;

Ringwald, Pascal ;

Silamut, Kamolrat ;

Imwong, Mallika ;

Chotivanich, Kesinee ;

Lim, Pharath ;

Herdman, Trent ;

An, Sen Sam ;

Yeung, Shunmay ;

Singhasivanon, Pratap ;

Day, Nicholas P. J. ;

Lindegardh, Niklas ;

Socheat, Duong ;

White, Nicholas J. .

NEW ENGLAND JOURNAL OF MEDICINE, 2009, 361 (05) :455-467

[5] Identification of a Metabolically Stable Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Antimalarial Activity in Mice [J].

Gujjar, Ramesh ;

Marwaha, Alka ;

El Mazouni, Farah ;

White, John ;

White, Karen L. ;

Creason, Sharon ;

Shackleford, David M. ;

Baldwin, Jeffrey ;

Charman, William N. ;

Buckner, Frederick S. ;

Charman, Susan ;

Rathod, Pradipsinh K. ;

Phillips, Margaret A. .

JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (07) :1864-1872

[6] The Plasmodium genome database -: Designing and mining a eukaryotic genomics resource [J].

Kissinger, JC ;

Brunk, BP ;

Crabtree, J ;

Fraunholz, MJ ;

Gajria, B ;

Milgram, AJ ;

Pearson, DS ;

Schug, J ;

Bahl, A ;

Diskin, SJ ;

Ginsburg, H ;

Grant, GR ;

Gupta, D ;

Labo, P ;

Li, L ;

Mailman, MD ;

Mcweeney, SK ;

Whetzel, P ;

Stoeckert, CJ ;

Roos, DS .

NATURE, 2002, 419 (6906) :490-492

[7] Thioredoxin reductase is essential for the survival of Plasmodium falciparum erythrocytic stages [J].

Krnajski, Z ;

Gilberger, TW ;

Walter, RD ;

Cowman, AF ;

Müller, S .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (29) :25970-25975

[8] Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings (Reprinted from Advanced Drug Delivery Reviews, vol 23, pg 3-25, 1997) [J].

Lipinski, CA ;

Lombardo, F ;

Dominy, BW ;

Feeney, PJ .

ADVANCED DRUG DELIVERY REVIEWS, 2001, 46 (1-3) :3-26

[9] Apicomplexan plastids as drug targets [J].

McFadden, GI ;

Roos, DS .

TRENDS IN MICROBIOLOGY, 1999, 7 (08) :328-333

[10] Outlook - Can open-source R&D reinvigorate drug research? [J].

Munos, Bernard .

NATURE REVIEWS DRUG DISCOVERY, 2006, 5 (09) :723-729

← 1 2 3 →