Abstract:

Cathepsins are a family of cystein proteases that is specifically expressed in the osteoclasts. They are responsible for terminal protein degradation in acidic environment, and therefore are involved in many serious human diseases, such as osteoporosis, osteoarthritis, and bone cancer and so on. Of all the 11 human cystein cathepsins, Cathepsin K is the predominant one as it is an important drug target and has gained special attention recently. According to the structural characteristics of the active site in cathepsin K, we designed and synthesized a series of dipeptide nitriles as inhibitors of cathepsins and have gained a potent and high selective inhibitor of it, b(K_i=15.9 nmol/L) and f(K_i=19.1 nmol/L). Inhibition activity was tested by measuring the hydrolysis of initially quenched fluorogenic peptide substrates. Studies on structure-activity relationship reveal large differences of 100-fold in activity suppression as a result of difference in NH linker between P₃ aryl and P₂ leucinamide moieties and P₃ moieties. Our results also suggest that less amide bonds may be good for the selectivity of peptide nitriles to cathepsins.

Key words: Cathepsin K; Peptide nitrile; Inhibitor; Structure-activity relationship