Ghymostatin, a New Ghymotrypsin Inhibitor Produced by Actinomygetes

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

“…1) Each cathepsin has different cleavage bond-specificity for substrate proteins, allowing induction of different physiological or pathological conditions. In general, the inhibitors for all cathepsins have been published and used, such as E-64, 2-4) leupeptin and antipain, 5,6) but no research has been published about specific inhibitors for individual cathepsins. We have developed specific inhibitors for individual cathepsins in cooperation with Asao (Taiho Pharmaceutical Co.), 7-10) by a structure-based new drug design method using X-ray crystallography of individual cathepsin structures (substrate binding pocket), with epoxysuccinate (E-64) as the frame compound.…”

Pepstatins: Aspartic proteinase inhibitors having potential therapeutic applications

“…In fact, the LD,, of this agent by an oral route was estimated to be higher than 2000 mg/kg in all the mammalian species evaluated. 15,17 Daily oral administrations of pepstatin in the range of 200-1000 mg/kg for up to 180 days did not cause any evident toxic effects either in rats or monkeys; nor did this agent induce teratogenic effects in pregnant mice and rats.I5,l7 Moreover, oral administrations of pepstatin at a dose level of 700 mg/kg up to 6 weeks to patients with peptic ulcer did not induce any evident…”

“…It is slightly soluble or insoluble in ethyl acetate, ether, benzene, chloroform, and water. 15 In previous studies, Barrett and Dingle19 showed that pepstatin binds tightly rabbit and human cathepsin D in an equimolar ratio. The dissociation constant was estimated to be less than l o p 8 M. In further investigations Knight and Barrett20 showed that the binding of pepstatin to human cathepsin D was strongly pH dependent.…”

A biomimetic domino reaction for the concise synthesis of capreomycidine and epicapreomycidine

“…Capreomycidine 1 can be found in tuberactinomycin peptide antibiotics (Nagata et al 1968; Wakamiya et al 1970; Yoshioka et al 1971; Ando et al 1971; Izumi et al 1972), e.g ., the capreomycins (Herr et al 1960; Bycroft et al 1971a; Shiba et al 1976; Nomoto et al 1977; Nomoto et al 1978) and viomycin 3 (Finlay et al 1951; Bartz et al 1951; Dyer et al 1965; Bycroft et al 1969; Noda et al 1972), which have both found clinical use as anti-tuberculosis drugs. The 3-epimer epicapreomycidine 2 is a component of the naturally occurring protease inhibitors chymostatin (Umezawa et al 1970; Tatsuta et al 1973) and elastatinal (Umezawa et al 1973; Okura et al 1975) as well as of the Streptomyces -produced muraymycins, a subclass of nucleoside lipopeptide antibiotics (e.g. muraymycin A1 4 , McDonald et al 2002).…”