For disease conditions such as Rheumatoid Arthritis, COPD, Inflammatory Bowel Disease, Asthma, Sepsis and Cystic Fibrosis several studies points to proteases, activated by DPPI, to be the cause of the disease. Thus, DPPI represents a new therapeutic target for the treatment of these inflammatory diseases.

The roles of DPPI and the granule-associated serine proteases, which it activates, have been assessed in a number of inflammation and other models using knockout mice:

• Rheumatoid Arthritis. DPPI knockout mice are completely resistant to acute arthritis induced by anti-type II collagen antibodies and showed a high degree of protection in a collagen-induced rheumatoid arthritis model. In both studies, the effects were attributed to a loss of neutrophil associated serine protease activities (elastase and cathepsin G) in the DPPI knockout animals.

• Asthma. The inflammatory response have been shown to be reduced in a neutrophil-dependent manner with DPPI knockout mice in a Sendai virus-induced asthma model

• COPD. Inappropriate neutrophil elastase activity is implicated in the development of chronic obstructive pulmonary disease (COPD) and DPPI knockout mice are resistant to lung airspace enlargement and inflammatory cell infiltration in both cigarette smoke and ozone exposure models of COPD.

• Sepsis. DPPI knockout mice show a significant protection from death in a cecal ligation and puncture model of sepsis. This protection was associated with the specific loss of mast cell DPPI and a resulting increase of the beneficial cytokine IL-6, which is normally degraded by mast cell tryptase

• Abdominal aortic aneurysms. A loss of neutrophil granule-associated serine protease activities (elastase and cathepsin G) was attributed to a reduction in vascular inflammation resulting in DPPI knockout mice being resistant to the development of elastase-induced experimental abdominal aortic aneurysms.

   

The crystal structures of native rat- and human DPPI as well as the first DPPI inhibitor complexes have been patented by Unizyme and Prozymex (a fully owned subsidiary of Unizyme). The aim of our current activities is to design, synthesize and characterize new DPPI inhibitors with the proper chemical and metabolic stability and pharmacokinetic profile useful for generating proof-of-concept in various animal disease models, for instance for rheumatoid arthritis.

Unizyme have recently discovered a new class of potent, specific and non-covalent DPPI inhibitors (IPR protected) with promising PK profiles in mice.