| Autor: |
O'Brien, Tom, Fahr, Bruce T., Sopko, Michelle M., Lam, Joni W., Waal, Nathan D., Raimundo, Brian C., Purkey, Hans E., Pham, Phuongly, Romanowski, Michael J. |
| Předmět: |
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| Zdroj: |
Acta Crystallographica: Section F (Wiley-Blackwell); May2005, Vol. 61 Issue 5, p451-458, 8p |
| Abstrakt: |
Caspase-1 is a key endopeptidase responsible for the post-translational processing of the IL-1β and IL-18 cytokines and small-molecule inhibitors that modulate the activity of this enzyme are predicted to be important therapeutic treatments for many inflammatory diseases. A fragment-assembly approach, accompanied by structural analysis, was employed to generate caspase-1 inhibitors. With the aid of Tethering® with extenders (small molecules that bind to the active-site cysteine and contain a free thiol), two novel fragments that bound to the active site and made a disulfide bond with the extender were identified by mass spectrometry. Direct linking of each fragment to the extender generated submicromolar reversible inhibitors that significantly reduced secretion of IL-1β but not IL-6 from human peripheral blood mononuclear cells. Thus, Tethering with extenders facilitated rapid identification and synthesis of caspase-1 inhibitors with cell-based activity and subsequent structural analyses provided insights into the enzyme's ability to accommodate different inhibitor-binding modes in the active site. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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