IUCr journals

Structural analysis of caspase-1 inhibitors derived from Tethering

Acta Cryst. (2005). F61, 451–458

[Caspase-1 with extender] Crystal structure of caspase-1 covalently modified with the extender. Hydrogen bonds between the extender and the protein are displayed as dashed yellow lines with their associated distances shown in black. Selected residues comprising the active site are also shown.
A fragment-assembly approach, accompanied by structural analysis, was employed to generate caspase-1 inhibitors with cell-based activity. 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 disulfi de bond with the extender were identifi ed by mass spectrometry. Direct linking of each fragment to the extender generated submicromolar, reversible inhibitors that significantly reduced secretion of the caspase-1-processed cytokine interleukin-1β from human peripheral blood mononuclear cells.

T. O’Brien, B. T. Fahr, M. M. Sopko, J. W. Lam, N. D. Waal, B. C. Raimundo, H. E. Purkey, P. Pham and M. J. Romanowski