Mammalian interleukin-1β. (IL-1β) plays an important role in various pathologic processes, including chronic and acute inflammation and autoimmune diseases. IL-1β is synthesized as a cell associated precursor polypeptide (pro-IL-1β) that is unable to bind IL-1 receptors and is biologically inactive. By inhibiting conversion of precursor IL-1β to mature IL-1β, the activity of interleukin-1 can be inhibited.
Interleukin-1β converting enzyme (ICE) is a protease responsible for the activation of interleukin-1β (IL-1β). ICE is a substrate-specific cysteine protease that cleaves the inactive prointerleukin-1 to produce the mature IL-1. The genes that encode for ICE and CPP32 are members of the mammalian ICE/Ced-3 family of genes which presently includes at least twelve members: ICE, CPP32/Yama/Apopain, mICE2, ICE4, ICH1, TX/ICH-2, MCH2, MCH3, MCH4, FLICE/MACH/MCH5, ICE-LAP6 and ICErel III. The proteolytic activity of this family of cysteine proteases, whose active site (a cysteine residue) is essential for ICE-mediated apoptosis, appears critical in mediating cell death (Miura et al., Cell 75:653–660 (1993)). This gene family has recently been named caspases (Alnernri et al., Cell, 87:171 (1996), and Thornberry et al., J. Biol. Chem. 272:17907–17911 (1997)) and divided into three groups according to its known functions.
Agents that modulate IL-1β activity have been shown to have beneficial in vivo effects. For example, compounds that are interleukin-1 receptor antagonists have been shown to inhibit ischemic and excitotoxic damage in rat brains (e.g., Relton et al. (1992) Brain Research Bulletin (1992) 29:243–246). Additionally, ICE inhibitors were shown to reduce inflammation and pyrexia in rats (Elford et al. (1995) British Journal of Pharmacology 115:601–606).
In addition to its effects on IL-1β, ICE has been shown to place a role in the production of the inflammatory mediator interferon-gamma (Ghayur et al. (1997) Nature 386:619–623). ICE processes the inactive proform of interferon-gamma (IGIF; interleukin-18) to active IGIF, a protein that induces production of interferon-gamma by T-cells and natural killer cells. Interferon-gamma has been implicated in the pathogenesis of diseases such as inflammatory disorders and septic shock. Therefore, inhibitors of caspase-1 would be expected to have beneficial effects in such disease states.
Many potent caspase inhibitors have been prepared based on the peptide substrate structures of caspases. However, the need exists for improved caspase-1 inhibitors. These inhibitors thus can be employed as therapeutic agents to treat disease states in which regulated cell death and the cytokine activity of IL-1 or IGIF play a role. Accordingly, it is an object of the present invention to provide methods and compositions useful in the inhibition of caspase-1.
USPTO Backgrounds
USPTO Backgrounds