Identification of inhibitors for putative malaria drug targets among novel antimalarial compounds.
The efficacy of most marketed antimalarial drugs has been compromised by evolution of parasite resistance, underscoring an urgent need to find new drugs with new mechanisms of action. We have taken a high-throughput approach toward identifying novel antimalarial chemical inhibitors of prioritized drug targets for Plasmodium falciparum, excluding targets which are inhibited by currently used drugs. A screen of commercially available libraries identified 5655 low molecular weight compounds that inhibit growth of P. falciparum cultures with EC(50) values below 1.25μM. These compounds were then tested in 384- or 1536-well biochemical assays for activity against nine Plasmodium enzymes: adenylosuccinate synthetase (AdSS), choline kinase (CK), deoxyuridine triphosphate nucleotidohydrolase (dUTPase), glutamate dehydrogenase (GDH), guanylate kinase (GK), N-myristoyltransferase (NMT), orotidine 5'-monophosphate decarboxylase (OMPDC), farnesyl pyrophosphate synthase (FPPS) and S-adenosylhomocysteine hydrolase (SAHH). These enzymes were selected using TDRtargets.org, and are believed to have excellent potential as drug targets based on criteria such as their likely essentiality, druggability, and amenability to high-throughput biochemical screening. Six of these targets were inhibited by one or more of the antimalarial scaffolds and may have potential use in drug development, further target validation studies and exploration of P. falciparum biochemistry and biology.
Crowther
Gregory J
GJ
University of Washington, Seattle, WA, USA.
Napuli
Alberto J
AJ
Gilligan
James H
JH
Gagaring
Kerstin
K
Borboa
Rachel
R
Francek
Carolyn
C
Chen
Zhong
Z
Dagostino
Eleanor F
EF
Stockmyer
Justin B
JB
Wang
Yu
Y
Rodenbough
Philip P
PP
Castaneda
Lisa J
LJ
Leibly
David J
DJ
Bhandari
Janhavi
J
Gelb
Michael H
MH
Brinker
Achim
A
Engels
Ingo H
IH
Taylor
Jennifer
J
Chatterjee
Arnab K
AK
Fantauzzi
Pascal
P
Glynne
Richard J
RJ
Van Voorhis
Wesley C
WC
Kuhen
Kelli L
KL
D000962:Antimalarials / Q000302:isolation & purification / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D004798:Enzymes / Q000378:metabolism; D057166:High-Throughput Screening Assays; D020128:Inhibitory Concentration 50; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors
D000962:Antimalarials; D004791:Enzyme Inhibitors; D004798:Enzymes; D015800:Protozoan Proteins
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