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 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.
authors.affiliation: Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: W Armand
authors.initials: WA
authors.lastname: Guiguemde
authors.forename: Anang A
authors.initials: AA
authors.lastname: Shelat
authors.forename: David
authors.initials: D
authors.lastname: Bouck
authors.forename: Sandra
authors.initials: S
authors.lastname: Duffy
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Crowther
authors.forename: Paul H
authors.initials: PH
authors.lastname: Davis
authors.forename: David C
authors.initials: DC
authors.lastname: Smithson
authors.forename: Michele
authors.initials: M
authors.lastname: Connelly
authors.forename: Julie
authors.initials: J
authors.lastname: Clark
authors.forename: Fangyi
authors.initials: F
authors.lastname: Zhu
authors.forename: María B
authors.initials: MB
authors.lastname: Jiménez-Díaz
authors.forename: María S
authors.initials: MS
authors.lastname: Martinez
authors.forename: Emily B
authors.initials: EB
authors.lastname: Wilson
authors.forename: Abhai K
authors.initials: AK
authors.lastname: Tripathi
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Sharlow
authors.forename: Ian
authors.initials: I
authors.lastname: Bathurst
authors.forename: Farah
authors.initials: F
authors.lastname: El Mazouni
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Fowble
authors.forename: Isaac
authors.initials: I
authors.lastname: Forquer
authors.forename: Paula L
authors.initials: PL
authors.lastname: McGinley
authors.forename: Steve
authors.initials: S
authors.lastname: Castro
authors.forename: Iñigo
authors.initials: I
authors.lastname: Angulo-Barturen
authors.forename: Santiago
authors.initials: S
authors.lastname: Ferrer
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Derisi
authors.forename: David J
authors.initials: DJ
authors.lastname: Sullivan
authors.forename: John S
authors.initials: JS
authors.lastname: Lazo
authors.forename: David S
authors.initials: DS
authors.lastname: Roos
authors.forename: Michael K
authors.initials: MK
authors.lastname: Riscoe
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Phillips
authors.forename: Pradipsinh K
authors.initials: PK
authors.lastname: Rathod
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Van Voorhis
authors.forename: Vicky M
authors.initials: VM
authors.lastname: Avery
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000032:analysis* / Q000302:isolation & purification / Q000494:pharmacology*; D002460:Cell Line; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004351:Drug Resistance / Q000187:drug effects; D004359:Drug Therapy, Combination; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D051379:Mice; D010641:Phenotype; D010802:Phylogeny; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D054852:Small Molecule Libraries