Targeting the fatty acid biosynthesis enzyme, β-ketoacyl - Acyl carrier protein synthase III (PfKASIII), in the identification of novel antimalarial agents

Patricia J. Lee, Jayendra B. Bhonsle, Heather W. Gaona, Donald P. Huddler, Tiffany N. Heady, Mara Kreishman-Deitrick, Apurba Bhattacharjee, William F. McCalmont, Lucia Gerena, Miriam Lopez-Sanchez, Norma E. Roncal, Thomas H. Hudson, Jacob D. Johnson, Sean T. Prigge, Norman C. Waters

Research output: Contribution to journalArticlepeer-review

Abstract

The importance of fatty acids to the human malaria parasite, Plasmodium falciparum, and differences due to a type I fatty acid synthesis (FAS) pathway in the parasite, make it an attractive drug target. In the present study, we developed and a utilized a pharmacophore to select compounds for testing against PfKASIII, the initiating enzyme of FAS. This effort identified several PfKASIII inhibitors that grouped into various chemical classes of sulfides, sulfonamides, and sulfonyls. Approximately 60% of the submicromolar inhibitors of PfKASIII inhibited in vitro growth of the malaria parasite. These compounds inhibited both drug sensitive and resistant parasites and testing against a mammalian cell line revealed an encouraging in vitro therapeutic index for the most active compounds. Docking studies into the active site of PfKASIII suggest a potential binding mode that exploits amino acid residues at the mouth of the substrate tunnel.

Original languageEnglish (US)
Pages (from-to)952-963
Number of pages12
JournalJournal of medicinal chemistry
Volume52
Issue number4
DOIs
StatePublished - Feb 26 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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