ORGN 453 |
| Caspases are thiol endopeptidases that cleave specific proteins after aspartic acid residues and drive apoptosis or inflammation upon zymogen activation. Despite considerable interest in developing active site inhibitors to these enzymes the highly charged nature of the substrate binding site has yielded relatively intractable chemotypes for drug discovery. We have discovered a novel allosteric site in both apoptotic capsases -3, and -7 and the inflammatory caspase-1. This involved the use of a site-directed fragment-based approach to drug discovery, called Tethering® or disulfide-trapping. In this case a native thiol at the dimer interface of caspases was allowed to react reversibly under thiol exchange conditions with a small library of disulfide-containing small molecules. The site-directed character of the approach can focus the discovery process on unactivated enzymes and allosteric sites which would otherwise be difficult to selectively target. We identified selective tethered compounds for these allosteric sites and will present their structures and mechanisms for inhibition (Hardy et al. PNAS 101, 12461 (2004); Scheer et al., PNAS 103,7579 (2006)). Mutational analysis reveals an “allosteric circuit” that connects these sites and we believe is naturally involved in their regulation. We have further developed chemical and immunologic tool that trap these transitions so they may be studied in vitro and in cells. |
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Ralph F. Hirschmann Award in Peptide Chemistry: Symposium in Honor of William F. DeGrado
9:00 AM-12:00 PM, Wednesday, April 9, 2008 Morial Convention Center -- La Nouvelle, Blrm. C, Oral
Division of Organic Chemistry |