Development of Selective Nitrile Inhibitors and ‘Activity-Based’ Probes For Human Cathepsins K and S

Abstract

Cysteine cathepsins show a high degree of similarity and play a significant role in many (patho)physiological processes such as bone remodeling, antigen presentation, osteoporosis, autoimmune disorders, and cancer. Therefore, cathepsins represent important targets for the development of new therapeutics and diagnostic tools. Inhibitors of cysteine cathepsins are mainly peptidic or peptidomimetic structures containing electrophilic groups prone to covalent interactions with the active-site cysteine. Among them, nitrile-based inhibitors receive the most attention in current drug discovery. The development of potent and selective nitrile inhibitors and fluorescent 'activity-based' probes for human cathepsins K and S is described in this dissertation.