Structure-based development of specific inhibitors for individual cathepsins and their medical applications.

Specific inhibitors for individual cathepsins have been developed based on their tertiary structures of X-ray crystallography. Cathepsin B-specific inhibitors, CA-074 and CA-030, and cathepsin L specific inhibitors, CLIK-148 and CLIK-195, were designed as the epoxysuccinate derivatives. Cathepsin S inhibitor, CLIK-060, and cathepsin K inhibitor, CLIK-166, were synthesized. These inhibitors can use in vitro and also in vivo, and show no toxicity for experimental animals by the amounts used as the cathepsin inhibitor. Various cathepsins are used in the processing of antigenic proteins. The CLIK-060 treatment to the autoimmune disease, Sjögren model mice, led to strongly suppress the expression of the pathological symptoms. Cathepsins L or K participates to the degradation of bone collagen. The CLIK-148 protects osteoporosis in animals and also protects the bone metastasis of cancer cells. Cathepsin L also enhances insulin-induced glucose uptake into 3T3-L1 adipocytes, suggesting cathepsin L plays the roles in adipogenesis and glucose tolerance in type 2 diabetes.