Chemical genetics of Plasmodium falciparum.
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.
Guiguemde
W Armand
WA
Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Shelat
Anang A
AA
Bouck
David
D
Duffy
Sandra
S
Crowther
Gregory J
GJ
Davis
Paul H
PH
Smithson
David C
DC
Connelly
Michele
M
Clark
Julie
J
Zhu
Fangyi
F
Jiménez-Díaz
María B
MB
Martinez
María S
MS
Wilson
Emily B
EB
Tripathi
Abhai K
AK
Gut
Jiri
J
Sharlow
Elizabeth R
ER
Bathurst
Ian
I
El Mazouni
Farah
F
Fowble
Joseph W
JW
Forquer
Isaac
I
McGinley
Paula L
PL
Castro
Steve
S
Angulo-Barturen
Iñigo
I
Ferrer
Santiago
S
Rosenthal
Philip J
PJ
Derisi
Joseph L
JL
Sullivan
David J
DJ
Lazo
John S
JS
Roos
David S
DS
Riscoe
Michael K
MK
Phillips
Margaret A
MA
Rathod
Pradipsinh K
PK
Van Voorhis
Wesley C
WC
Avery
Vicky M
VM
Guy
R Kiplin
RK
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
D000962:Antimalarials; D054852:Small Molecule Libraries