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.
Autoimmune diseases, such as Crohn’s disease, SLE and psoriasis, occur when the body’s immune system mistakenly attacks healthy normal tissues. Cathepsin S performs a key step early in the development of autoimmune disease by activating a type of cell, CD4+ T, critical to the function of the immune system which is inappropriately activated in disease. When this step is blocked by a cathepsin S inhibitor, CD4+ T cells are not activated, and the autoimmune disease dependent on their activity is suppressed.
The specific step that cathepsin S performs is the cleavage of a protein called the invariant chain. Cleaving the invariant chain is a critical and necessary step in enabling the assembly of a specific cell surface protein receptor known as MHC Class II, which activates CD4+ T cells. Inhibition of cathepsin S activity will block this process and assembly of the receptor, preventing the activation of CD4+ T cells. We use biomarkers of this process to determine the level of cathepsin S inhibition and as such, guide dosing. Cathepsin S inhibition will not block other pathways of the immune system, including the pathways involved in the protective response against viruses. We believe that cathepsin S inhibitors such as VBY-036 will block the cleavage of the invariant chain, thereby suppressing autoimmune disease without fully suppressing the immune system.