In vitro and in vivo studies of ICE inhibitors.
Interleukin-1 beta-converting enzyme (ICE) is a cysteine protease responsible for proteolytic activation of the biologically inactive interleukin-1 beta precursor to the proinflammatory cytokine. ICE and homologous proteases also appear to mediate intracellular protein degradation during programmed cell death. Inhibition of ICE is a new antiinflammatory strategy being explored by the design of both reversible inhibitors and irreversible inactivators of the enzyme. Such compounds are capable of blocking release of interleukin-1 beta from human monocytes. ICE inhibitors that cross react against multiple ICE homologs can also block apoptosis in diverse cell types. ICE inhibitors impart protection in vivo from endotoxin-induced sepsis and collagen-induced polyarthritis in rodent models. Further optimization of the current generation of peptidyl ICE inhibitors will be required to produce agents suitable for administration in chronic inflammatory and neurodegenerative diseases.
Livingston
D J
DJ
Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts 02139, USA.
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020170:Caspase 1; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000145:classification* / Q000494:pharmacology*; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D005544:Forecasting; D006801:Humans
D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D003546:Cysteine Endopeptidases; D020170:Caspase 1