Summary

• Proteases catalyse the hydrolyis of peptide bonds in proteins, often in a very precise way, and are thereby involved in the control of a number of important physiological processes including cell-cycle progression, DNA replication, cell proliferation and cell death, as well as the immune response
• Protease signalling varies from a simple direct cleavage of a substrate to a complex cascade organization or a protease network, and requires tight regulation
• Excessive proteolytic activity often leads to disease but can be prevented by blocking the appropriate proteases, which has been explored therapeutically since the 1950s.
• Angiotensin-converting enzyme (ACE) inhibitors, which were introduced in 1981 for the treatment of various cardiovascular diseases (hypertension, heart failure, heart attack and so on), are still the major blockbusters among protease inhibitors on the market. On the other hand, various broad-spectrum matrix metalloprotease (MMP) inhibitors failed in advanced clinical trials for cancer and rheumatoid arthritis treatment in the 1990s because of various drawbacks.
• Identification of endogenous protease substrates and other physiological protease ligands is a key issue in understanding protease signalling pathways and an essential part of the identification and validation of protease targets
• Therapeutic inhibition of validated protease targets can be achieved either by large or small molecules. Large-molecule approaches include protein-type inhibitors that mimick physiological inhibitors and neutralizing antibodies. The development of small-molecule inhibitors, however, is by far the most popular approach. An ideal inhibitor would be a non-covalent, reversible inhibitor with excellent selectivity, good bioavailability and no side effects. The major issues in inhibitor design are still bioavailability and toxicity.
• The most advanced inhibitors in clinical trials are the renin inhibitors aliskiren (SPP100) for the treatment of hypertension and end-organ damage for which an NDA was filed in 2006, and the dipeptidyl peptidase IV (DPP IV) inhibitors sitagliptin (MK-0431) and vildagliptin (LAF 327) for the treatment of type 2 diabetes, for which NDAs were also filed in 2006. Balicatib (AAE581), the most advanced among the cathepsin K inhibitors for osteoporosis treatment, successfully passed Phase II trials in 2005. Diabetes type 2 and osteoporosis are completely new therapeutic areas, which is encouraging for the future.
• Proteases, such as kallikrein 3 (prostate-specific antigen) and plasminogen activator, are important diagnostic and prognostic disease markers.
• The future of protease-based drug discovery efforts probably lies in the cardiovascular, inflammatory, infectious disease, cancer and neurodegeneration areas.