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- Title
In situ assembly of enzyme inhibitors using extended tethering.
- Authors
Erlanson, Daniel A.; Lam, Joni W.; Wiesmann, Christian; Luong, Tinh N.; Simmons, Robert L.; DeLano, Warren L.; Choong, Ingrid C.; Burdett, Matthew T.; Flanagan, W. Michael; Lee, Dennis; Gordon, Eric M.; O'Brien, Tom
- Abstract
Cysteine aspartyl protease-3 (caspase-3) is a mediator of apoptosis and a therapeutic target for a wide range of diseases. Using a dynamic combinatorial technology, 'extended tethering', we identified unique nonpeptidic inhibitors for this enzyme. Extended tethering allowed the identification of ligands that bind to discrete regions of caspase-3 and also helped direct the assembly of these ligands into small-molecule inhibitors. We first designed a small-molecule 'extender' that irreversibly alkylates the cysteine residue of caspase-3 and also contains a thiol group. The modified protein was then screened against a library of disulfide-containing smallmolecule fragments. Mass-spectrometry was used to identify ligands that bind noncovalently to the protein and that also form a disulfide linkage with the extender. Linking the selected fragments with binding elements from the extenders generates reversible, tight-binding molecules that are druglike and distinct from known inhibitors. One molecule derived from this approach inhibited apoptosis in cells.
- Subjects
PROTEOLYTIC enzymes; ENZYME inhibitors; LIGANDS (Biochemistry)
- Publication
Nature Biotechnology, 2003, Vol 21, Issue 3, p308
- ISSN
1087-0156
- Publication type
Article
- DOI
10.1038/nbt786