Novel Small-Molecule Inhibitors of Anthrax Lethal Factor Identified by High-Throughput Screening

Igor A. Schepetkin,† Andrei I. Khlebnikov,‡ Liliya N. Kirpotina,† and Mark T. Quinn*†
Department of Veterinary Molecular Biology, Montana State University, Bozeman, Montana 59717, and Department of Chemistry, Altai State Technical University, Barnaul 656038, Russia
J. Med. Chem., 2006, 49 (17), pp 5232–5244
DOI: 10.1021/jm0605132
Publication Date (Web): July 28, 2006
Copyright © 2006 American Chemical Society
†

 Montana State University.

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‡

 Altai State Technical University.

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*

 To whom correspondence should be addressed. Phone:  406-994-5721. Fax:  406-994-4303. E-mail:  mquinn@montana.edu.

Abstract

Abstract Image

Anthrax lethal factor (LF) is a key virulence factor of anthrax lethal toxin. We screened a chemolibrary of 10 000 drug-like molecules for their ability to inhibit LF and identified 18 novel small molecules with potent LF inhibitory activity. Three additional LF inhibitors were identified through further structure−activity relationship (SAR) analysis. All 21 compounds inhibited LF with an IC50 range of 0.8 to 11 μM, utilizing mixed-mode competitive inhibition. An evaluation of inhibitory activity against a range of unrelated proteases showed relatively high specificity for LF. Furthermore, pharmacophore modeling of these compounds showed a high degree of similarity to the model published by Panchal et al. (Nat. Struct. Mol. Biol. 2004, 11, 67−72), indicating that the conformational features of these inhibitors are structurally compatible with the steric constraints of the substrate-binding pocket. These novel LF inhibitors and the structural scaffolds identified as important for inhibitory activity represent promising leads to pursue for further LF inhibitor development.

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History

  • Published In Issue August 24, 2006
  • Received May 1, 2006

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