Proceedings of the Japan Academy, Series B

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Discovered in the late-1970s, the pioneering drug ivermectin, a dihydro derivative of avermectin—originating solely from a single microorganism isolated at the Kitasato Intitute, Tokyo, Japan from Japanese soil—has had an immeasurably beneficial impact in improving the lives and welfare of billions of people throughout the world. Originally introduced as a veterinary drug, it kills a wide range of internal and external parasites in commercial livestock and companion animals. It was quickly discovered to be ideal in combating two of the world’s most devastating and disfiguring diseases which have plagued the world’s poor throughout the tropics for centuries. It is now being used free-of-charge as the sole tool in campaigns to eliminate both diseases globally. It has also been used to successfully overcome several other human diseases and new uses for it are continually being found. This paper looks in depth at the events surrounding ivermectin’s passage from being a huge success in Animal Health into its widespread use in humans, a development which has led many to describe it as a “wonder” drug.

(Contributed by Satoshi OMURA, M.J.A.)

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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.

(Communicated by Takao SEKIYA, M.J.A.)

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