Protease Inhibitor Platform

Proteases in pathology
Proteases play a key role in many pathological processes and dysregulation of proteases plays a role in such diverse diseases as cancer, rheumatoid arthritis, cardiovascular diseases, microbial infections or Alzheimer’s disease. Nevertheless, only very few effective protease inhibitors are available today (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.

The human tissue kallikrein gene family (KLK) is the largest cluster of proteases in the human genome. Kallikreins are produced by a wide range of tissues where they are implicated in diverse physiological functions, including skin desquamation, blood pressure regulation or semen liquefaction. Beside their established role as biomarkers for various carcinomas including prostate cancer, kallikreins are considered promising drug targets in pathological conditions where their proteolytic activity is dysregulated such as prostatic diseases, skin disorders, and various cancers.

Protease core technology
Serpin (serine protease inhibitor) proteins inhibit a specific protease or class of proteases by formation of a stable, covalent complex with their target. Our antiprotease technology is based on the modification of natural, serpin-type protease inhibitors to improve or change their specificity. As the inhibitor scaffold is natural, our technology allows the generation of leads with a promising safety profile compare to chemical ones.

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

The strategy adopted by Med Discovery to develop protease inhibitors is divided into two major steps:
- The first step consists of selecting substrate peptides, kinetic analysis of these and identification of first generation leads
- In a second step, the selected peptide sequences are used to modify serpin proteins permitting the development of specific inhibitors for target proteases

Our antiprotease technology platform has been successfully applied to develop selective inhibitors against a panel of proteases with divergent specificities. Examples include proteases with a potential in oncology, e.g. various kallikreins (for published papers see PMID: 14728688; PMID: 16704423), but also proteases which are involved in other pathological processes such as inflammation.