Cathepsins are a family of proteases that have been implicated in many diseases.
Virobay compounds are highly potent, orally active and drug-like; addressing common problems in the design of cathepsin inhibitors.
Autoimmune disease is characterized by an overactive immune response, presumably against endogenous antigens presented by the immune system. Autoimmune diseases include organ-specific diseases such as rheumatoid arthritis, psoriasis and psoriatic arthritis, multiple sclerosis, type I diabetes, inflammatory bowel disease (IBD), and non-specific disorders such as lupus (SLE). All of these diseases show aberrant immunological tolerance toward self antigens. Such immune-mediated diseases affect several millions of people worldwide and result in high medical and social costs.
Cathepsin S is expressed in professional antigen presenting cells (APCs) but can also be found in non-professional APCs, such as keratinocytes, synoviocytes, and intestinal epithelial cells, particularly under conditions of immune activation and inflammation. In autoimmune diseases, cathepsin S is implicated in the major histocompatibilitiy complex (MHC) Class II-dependent presentation of self-antigens to autoreactive CD4+ T cells.
A chaperone-like protein called invariant chain binds to the peptide-binding groove of the MHC Class II molecule. Invariant chain serves to temporarily occupy the peptide-binding groove of MHC Class II as well as target the receptor to the appropriate cellular compartment for antigenic peptide loading. Cleavage of the invariant chain occurs through proteolysis to a 10 kilodalton intermediate (Iip10), followed by cleavage to form the key 24-amino acid fragment Class II associated invariant chain peptide (CLIP). While a number of proteases have been implicated in cleaving the invariant chain, in key antigen presenting cells including B cells and dendritic cells cathepsin S appears to be the single critical enzyme in the final step of invariant chain processing. Once CLIP is formed, an MHC-like molecule HLA-DM replaces the MHC Class II-bound CLIP peptide with an antigenic peptide. The resulting antigen-loaded MHC Class II molecule is transported to the cell surface where the complex is presented to compatible CD4+ T cells that then become activated.
Cathepsin S inhibitors should have efficacy in diseases in which CD4+ T cells are activated via MHC Class II-antigen presentation such as rheumatoid arthritis, psoriasis, Crohn’s disease/IBD, multiple sclerosis, type I diabetes, etc.
Proprietary Virobay data