Based on the discovery of selective and potent human neutrophil elastase inhibitors like POL6014 Polyphor has extended its protease research program to include other serine and cystein proteases. Proteases are a well defined class of enzymes involved in many different diseases, especially of the respiratory tract and the cardiovascular system, e.g. hypertension and coagulation disorders. Initially, most of Polyphor`s screening efforts had been focused on serine proteases; recently a cystein protease (cathepsin C) was also included. This systematic screening approach has yielded several potent and selective inhibitors, e.g. against the serine proteases chymase, prostasin, tryptase, kallikrein and cathepsin G and the cystein protease cathepsin C. In addition to selective inhibitors, these efforts have also resulted in dual or triple inhibitors against related proteases (e.g. neutrophil elastase and proteinase 3, prostasin and matriptase). Such inhibitors of more than one protease might provide therapeutic benefits compared to single and selective inhibitors if they target related proteases involved in the same disease (e.g. neutrophil elastase and proteinase 3 for respiratory diseases).
Cystein proteases (cathepsin C, caspases) are notoriously difficult targets for small molecule inhibitors because many small molecule inhibitors bind covalently to the cystein in the active site. It is noteworthy that Polyphor has readily identified competitive inhibitors of a cystein protease in the PEM library.
In the lead optimization process of proteases Polyphor takes advantage of its capabilities in protein expression and X-ray crystallography. Knowledge of the 3D structure and binding of the PEM molecule to the active site has greatly enhanced the lead optimization process in several projects.