Journal article
A Chemical Genomic Analysis of Decoquinate, a Plasmodium falciparum Cytochrome b Inhibitor
ACS chemical biology, v 6(11), pp 1214-1222
18 Nov 2011
PMID: 21866942
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Decoquinate has single-digit nanomolar activity against
in vitro
blood stage
Plasmodium falciparum
parasites, the causative agent of human malaria.
In vitro
evolution of decoquinate-resistant parasites and subsequent comparative genomic analysis to the drug-sensitive parental strain revealed resistance was conferred by two nonsynonymous single nucleotide polymorphisms in the gene encoding cytochrome
b
. The resultant amino acid mutations, A122T and Y126C, reside within helix C in the ubiquinol-binding pocket of cytochrome
b
, an essential subunit of the cytochrome
bc
1
complex. As with other cytochrome
bc
1
inhibitors, such as atovaquone, decoquinate has low nanomolar activity against
in vitro
liver stage
P. yoelii
and provides partial prophylaxis protection when administered to infected mice at 50 mg kg
–1
. In addition, transgenic parasites expressing yeast dihydroorotate dehydrogenase are >200-fold less sensitive to decoquinate, which provides additional evidence that this drug inhibits the parasite’s mitochondrial electron transport chain. Importantly, decoquinate exhibits limited cross-resistance to a panel of atovaquone-resistant parasites evolved to harbor various mutations in cytochrome
b
. The basis for this difference was revealed by molecular docking studies, in which both of these inhibitors were shown to have distinctly different modes of binding within the ubiquinol-binding site of cytochrome
b
.
Metrics
Details
- Title
- A Chemical Genomic Analysis of Decoquinate, a Plasmodium falciparum Cytochrome b Inhibitor
- Creators
- Tae-gyu Nam - Department of Chemistry andCase W McNamara - , 10675 John Jay Hopkins Drive, San Diego, California 92121, United StatesSelina Bopp - Department of Chemistry andNeekesh V Dharia - Department of Chemistry andStephan Meister - Department of Chemistry andGhislain M. C Bonamy - , 10675 John Jay Hopkins Drive, San Diego, California 92121, United StatesDavid M Plouffe - , 10675 John Jay Hopkins Drive, San Diego, California 92121, United StatesNobutaka Kato - , 10675 John Jay Hopkins Drive, San Diego, California 92121, United StatesSusan McCormack - , 10675 John Jay Hopkins Drive, San Diego, California 92121, United StatesBadry Bursulaya - , 10675 John Jay Hopkins Drive, San Diego, California 92121, United StatesHangjun Ke - Center for Molecular Parasitology, Department of Microbiology and ImmunologyAkhil B Vaidya - Center for Molecular Parasitology, Department of Microbiology and ImmunologyPeter G Schultz - Department of Chemistry andElizabeth A Winzeler - Department of Chemistry and
- Publication Details
- ACS chemical biology, v 6(11), pp 1214-1222
- Publisher
- American Chemical Society; Washington, DC
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000297038800010
- Scopus ID
- 2-s2.0-81555228431
- Other Identifier
- 991014878037204721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology