A Chemical Genomic Analysis of Decoquinate, a Plasmodium falciparum Cytochrome b Inhibitor

• DOI: 10.1021/cb200105d
• Publication Date: 2011-08-25T18:52:05Z
• Authors: Tae-gyu Nam; Case W. McNamara; Selina Bopp; Neekesh V. Dharia; Stephan Meister; Ghislain M. C. Bo...; David M. Plouffe; Nobutaka Kato; Susan McCormack; Badry Bursulaya; Hangjun Ke; Akhil B. Vaidya; Peter G. Schultz; Elizabeth A. Winz...
• Keywords: Atovaquone; Ubiquinol; Cytochrome C1

Decoquinate has single-digit nanomolar activity against in vitro blood stage Plasmodium falciparum parasites, the causative agent of human malaria. In evolution decoquinate-resistant parasites and subsequent comparative genomic analysis to drug-sensitive parental strain revealed resistance was conferred by two nonsynonymous single nucleotide polymorphisms gene encoding cytochrome b. The resultant amino acid mutations, A122T Y126C, reside within helix C ubiquinol-binding pocket b, an essential subunit bc1 complex. As with other inhibitors, such as atovaquone, decoquinate low liver P. yoelii provides partial prophylaxis protection when administered infected mice at 50 mg kg–1. addition, transgenic expressing yeast dihydroorotate dehydrogenase are >200-fold less sensitive decoquinate, which additional evidence that this drug inhibits parasite's mitochondrial electron transport chain. Importantly, exhibits limited cross-resistance a panel atovaquone-resistant evolved harbor various mutations basis for difference molecular docking studies, both these inhibitors were shown have distinctly different modes binding site