Structural analysis of caspase-1 inhibitors derived from Tethering

Acta Crystallogr Sect F Struct Biol Cryst Commun. 2005 May 1;61(Pt 5):451-8. doi: 10.1107/S1744309105010109. Epub 2005 Apr 9.


Caspase-1 is a key endopeptidase responsible for the post-translational processing of the IL-1beta 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-1beta 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Binding Sites / drug effects
  • Caspase 1 / chemistry
  • Caspase Inhibitors*
  • Combinatorial Chemistry Techniques / methods*
  • Crystallography, X-Ray
  • Cysteine Proteinase Inhibitors / chemistry*
  • Cysteine Proteinase Inhibitors / metabolism
  • Cysteine Proteinase Inhibitors / pharmacology
  • Drug Design
  • Humans
  • Interleukin-1 / antagonists & inhibitors
  • Interleukin-1 / blood
  • Interleukin-6 / antagonists & inhibitors
  • Interleukin-6 / blood
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / enzymology
  • Leukocytes, Mononuclear / metabolism
  • Models, Molecular
  • Protein Binding / drug effects
  • Solubility


  • Caspase Inhibitors
  • Cysteine Proteinase Inhibitors
  • Interleukin-1
  • Interleukin-6
  • Caspase 1

Associated data

  • PDB/1RWK
  • PDB/1RWM
  • PDB/1RWN
  • PDB/1RWO
  • PDB/1RWP