Discovery of a small molecule that inhibits the interaction of anthrax edema factor with its cellular activator, calmodulin

Young Sam Lee, Pamela Bergson, Wei Song He, Milan Mrksich*, Wei Jen Tang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

The catalytic efficiency of adenylyl cyclase activity of edema factor (EF) from Bacillus anthracis is enhanced by approximately 1000-fold upon its binding to mammalian protein calmodulin (CaM). A tandem cell-based and protein binding-based screen of a 10,000 member library identified a molecule that inhibits the EF-CaM interaction and therefore the adenylyl cyclase activity. A combination of fluorescence spectroscopy and photolabeling studies showed that the molecule targets the CaM binding region of EF. A series of related compounds were synthesized and evaluated to identify one compound, 4-[4-(4-nitrophenyl)- thiazolylamino]-benzenesulfonamide, that maintained activity against EF but showed minimal toxicity to two cultured cell lines. This compound represents an important reagent to study the role of EF in anthrax pathology and may represent a drug lead against anthrax infection.

Original languageEnglish (US)
Pages (from-to)1139-1146
Number of pages8
JournalChemistry and Biology
Volume11
Issue number8
DOIs
StatePublished - Aug 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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