Antiprotease technology

Proteases play a key role in many pathological processes and dysregulation thereof plays a role in such diverse diseases as cancer, rheumatoid arthritis, cardiovascular diseases, microbial infections or Alzheimer’s disease and the recent analysis of the human genome identified over 500 different proteases. Nevertheless, only very few effective protease inhibitors are today available (mostly inhibitors against Angiotensin Converting Enzyme ACE or the HIV protease) and selectivity and toxic side effects turned out to be major problems in the development of protease inhibitors.

Our antiprotease technology is based on the modification of natural, serpin-type protease inhibitors. Serpin (serine protease inhibitor) proteins inhibit a specific protease or class of proteases by formation of a stable, covalent complex with their target.

Conversion of a natural inhibitor into a selective lead for inhibiting a therapeutic target

Selectivity of these inhibitors is mostly attributed to a short amino acid sequence, which is presented to the target protease on a flexible loop. This reactive serpin loop (RSL) serves as substrate for the protease. Cleavage of the RSL by the protease triggers a conformational change within the serpin protein and traps both molecules in a stable covalent complex The modification of the RSL sequence changes activity and selectivity of the inhibitor. We use phage display technology to select short polypeptide sequences with high selectivity towards a target protease. Subsequently, these substrate sequences are introduced into the RSL domain of a natural serpin protein to create new, highly active and selective protease inhibitors.