Cathepsin S is considered crucial for normal presentation of major histocompatibility complex (MHC) class II-restricted antigens by antigen presenting cells to CD4 ϩ T cells. It is a key enzyme for the degradation of the class II-associated invariant chain, a process that is required for effective antigen loading of class II molecules. Here, we report a selective, orally available, high-affinity cathepsin S inhibitor, 1-, that represents a novel class of immunosuppressive compounds. JNJ 10329670 is a highly potent (K i of ϳ30 nM), nonpeptidic, noncovalent inhibitor of human cathepsin S, but it is much less active against the mouse, dog, monkey, and bovine enzymes. The compound is inactive against other proteases, including the closely related cathepsins L, F, and K. This selectivity makes JNJ 10329670 an excellent tool for exploring the role of cathepsin S in human systems. Treatment of human B cell lines and primary human dendritic cells with JNJ 10329670 resulted in the accumulation of the p10 fragment of the invariant chain (IC 50 of ϳ1 M). In contrast, inhibition of invariant chain proteolysis was much less effective in a human monocytic cell line, suggesting that other enzymes may degrade the invariant chain in this cell type. JNJ 10329670 was shown to block the proteolysis of the invariant chain in vivo by using immunocompromised mice injected with human peripheral blood mononuclear cells (PBMCs). Furthermore, this inhibitor blocks the presentation of tetanus toxoid and giant ragweed by human PBMCs. The properties of JNJ 10329670 make it a candidate for immunosuppressive therapy of allergies and autoimmune diseases.
The presentation of antigens by MHC class II (MHC II) molecules is the crucial initiating step in a CD4ϩ T cellmediated immune response. Antigen presenting cells, mainly dendritic cells, B cells, and macrophages, take up and present antigens from the extracellular environment. The internalized protein antigens are processed by endosomal or lysosomal proteases to generate peptides that become associated with MHC II molecules. Peptide-loaded MHC II molecules are subsequently transported to the cell surface for display to CD4 ϩ T cells. Recognition of the MHC II/peptide complexes triggers the activation of antigen-specific CD4 ϩ T cells, which in turn activate other components of the immune system such as B cells, macrophages, and CD8 ϩ T cells. These cellular responses are crucial for the body's response to pathogens, but they are also responsible for the development and symptoms of allergy and autoimmune disease.Cathepsin S is a cysteine protease found in the lysosome of hematopoietic cells. It is a member of the papain superfamily and has 57% identity to cathepsins L and K. Unlike most other lysosomal proteases that are only active under acidic conditions, the activity of cathepsin S exhibits a broad pH optimum that extends to alkaline pH. In contrast to the housekeeping enzymes cathepsins B, D, and L, which are expressed ubiquitously, cathepsin S is expressed mainly in dendritic cells,...