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A chemical genomic analysis of decoquinate, a plasmodium falciparum cytochrome b inhibitor

Academic Article
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Overview

related to degree

  • Dharia, Neekesh, Ph.D. in Biology, Scripps Research 2005 - 2009

authors

  • Nam, T. G.
  • McNamara, C. W.
  • Bopp, S.
  • Dharia, Neekesh
  • Meister, S.
  • Bonamy, G. M. C.
  • Plouffe, D. M.
  • Kato, N.
  • McCormack, S.
  • Bursulaya, B.
  • Ke, H. J.
  • Vaidya, A. B.
  • Schultz, Peter
  • Winzeler, Elizabeth

publication date

  • November 2011

journal

  • ACS Chemical Biology  Journal

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.

subject areas

  • Animals
  • Antimalarials
  • Crystallography, X-Ray
  • Cytochromes b
  • Decoquinate
  • Drug Discovery
  • Drug Resistance, Fungal
  • Female
  • Humans
  • Mice
  • Mice, Inbred ICR
  • Models, Molecular
  • Molecular Structure
  • Parasitic Sensitivity Tests
  • Plasmodium falciparum
  • Structure-Activity Relationship
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Identity

PubMed Central ID

  • PMC3220786

International Standard Serial Number (ISSN)

  • 1554-8929

Digital Object Identifier (DOI)

  • 10.1021/cb200105d

PubMed ID

  • 21866942
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Additional Document Info

start page

  • 1214

end page

  • 1222

volume

  • 6

issue

  • 11

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