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Biotech / Medical : New Brunswick Scientific Co., Inc. (NBSC) -- Ignore unavailable to you. Want to Upgrade?

To: scaram(o)uche who wrote (619)	2/5/2003 2:07:36 PM
From: scaram(o)uche	Respond to of 724

here's the abstract........ Published online: 3 February 2003, doi:10.1038/nbt786 In situ assembly of enzyme inhibitors using extended tethering Daniel A. Erlanson, Joni W. Lam, Christian Wiesmann, Tinh N. Luong, Robert L. Simmons, Warren L. DeLano, Ingrid C. Choong, Matthew T. Burdett, W. Michael Flanagan, Dennis Lee, Eric M. Gordon & Tom O'Brien Sunesis Pharmaceuticals, Inc., 341 Oyster Point Boulevard, South San Francisco, CA 94080. Correspondence should be addressed to D A Erlanson. e-mail: erlanson@sunesis.com and T O O'Brien. e-mail: 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 small-molecule 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.

To: scaram(o)uche who wrote (619)	3/12/2003 9:11:38 AM
From: nigel bates	Read Replies (1) \| Respond to of 724

Sunesis If they can do this... Message 18689503 ...In addition, as reported in the PNAS study, the Company's scientists found adaptive sites in the target protein that are not evident upon inspection of x-ray crystal structure data of the native protein. They report that the IL-2 protein surface changed its conformation in the presence of tethered fragments. Dr. Wells commented, "These observations underscore the value and potential of an empirical process like Tethering to probe for adaptive binding sites on a target. Traditional structure-based approaches often do not provide sufficient insight for progressing potent leads against these more challenging but highly relevant disease targets."