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

Research output: Contribution to journalArticlepeer-review

32 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
Pages (from-to)1139-1146
Number of pages8
JournalChemistry and Biology
Volume11
Issue number8
DOIs
StatePublished - Aug 2004

Bibliographical note

Funding Information:
This work was supported by the NSF MRSEC and NIH (GM53459, GM62548). Y.S.L. was supported by the Burroughs Wellcome Fund Interfaces in Science Fellowship. P.B. was supported by the Erma Smith Scholarship in Physiology and by an NSERC predoctoral fellowship. We thank S. Soelaiman for technical assistance, B. Shoichet (University of California, San Francisco) for providing enzymes, and M. Brown (University of Virginia) for sharing the unpublished toxicity studies of phenylthiazole analogs. Fluorescence experiments were done in the Biophysics Core Facility at the University of Chicago.

ASJC Scopus subject areas

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

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