Abstract
Recent events have created an urgent need for new therapeutic strategies to treat anthrax. We have applied a mixture-based peptide library approach to rapidly determine the optimal peptide substrate for the anthrax lethal factor (LF), a metalloproteinase with an important role in the pathogenesis of the disease. Using this approach we have identified peptide analogs that inhibit the enzyme in vitro and that protect cultured macrophages from LF-mediated cytolysis. The crystal structures of LF bound to an optimized peptide substrate and to peptide-based inhibitors provide a rationale for the observed selectivity and may be exploited in the design of future generations of LF inhibitors.
Publication types
- Research Support, U.S. Gov't, Non-P.H.S.
- Research Support, U.S. Gov't, P.H.S.
MeSH terms
- Amino Acid Motifs
- Amino Acid Sequence
- Anthrax / drug therapy
- Antigens, Bacterial*
- Bacillus anthracis / enzymology
- Bacillus anthracis / genetics
- Bacillus anthracis / pathogenicity*
- Bacterial Toxins / antagonists & inhibitors*
- Bacterial Toxins / genetics
- Bacterial Toxins / metabolism*
- Humans
- In Vitro Techniques
- Kinetics
- Macromolecular Substances
- Metalloendopeptidases / antagonists & inhibitors
- Metalloendopeptidases / genetics
- Metalloendopeptidases / metabolism
- Models, Molecular
- Molecular Sequence Data
- Oligopeptides / chemistry
- Oligopeptides / pharmacology
- Peptide Library
- Substrate Specificity
Substances
- Antigens, Bacterial
- Bacterial Toxins
- Macromolecular Substances
- Oligopeptides
- Peptide Library
- anthrax toxin
- Metalloendopeptidases
Associated data
- PDB/1PWQ
- PDB/1PWU
- PDB/1PWV
- PDB/1PWW