Dipeptidyl peptidase I (cathepsin C)

- a novel target for the treatment of inflammatory diseases

 

UNIZYME Laboratories designs, optimises and develops novel small-molecule inhibitors of dipeptidyl peptidase I (DPPI; also known as cathepsin C) – an enzyme involved in inflammatory diseases.
 

DPPI functions as a key enzyme in the activation of granule serine peptidases in inflammatory cells, such as elastase and cathepsin G in neutrophils cells and chymase and tryptase in mast cells. In many important diseases a significant part of the pathogenesis is caused by the increased activity of some of these inflammatory proteases. Once activated by DPPI, the proteases are capable of degrading various extracellular matrix components, which can lead to tissue damage and chronic inflammation.

 

For disease conditions such as Rheumatoid Arthritis, COPD, Inflammatory Bowel Disease, Asthma, Sepsis and Cystic Fibrosis several studies points to proteases, activated by DPPI, as being 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 models as well as 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 has 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 aim of our current activities is to design, synthesise and characterise 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 in rheumatoid arthritis.

 

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

 

 
 

 

 

 

Unizyme Laboratories welcomes partners who will participate in the continued development of DPPI inhibitors. Contact: John Pedersen.

 

October 2010