Abstract
WF14865A and B, novel cathepsins B and L inhibitors, were produced and isolated separately from the culture mycelium of a fungal strain Aphanoascus fulvescens No. 14865. Spectroscopic analysis revealed that both WF14865A and B were composed of trans-epoxysuccinyl moieties, 1-H-imidazole-2-ylamine, and isoleucine or leucine. These compounds inhibited human cathepsins B and L with IC50 values in the range of 8.4 approximately 72nM in vitro. Though their in vitro properties were typical as trans-epoxysuccinyl type inhibitors, they exerted strong bone resorption inhibitory effects in low-calcium-diet-fed mouse model at 3.2 approximately 10 mg/kg.
MeSH terms
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Animals
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Ascomycota / metabolism*
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Cathepsin B / antagonists & inhibitors*
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Cathepsin L
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Cathepsins / antagonists & inhibitors*
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Chromatography, Liquid
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Cysteine Endopeptidases
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Cysteine Proteinase Inhibitors / classification*
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Cysteine Proteinase Inhibitors / isolation & purification
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Cysteine Proteinase Inhibitors / pharmacology
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Endopeptidases*
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Epoxy Compounds / chemistry*
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Epoxy Compounds / isolation & purification
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Epoxy Compounds / pharmacology
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Female
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Humans
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Isoleucine / analogs & derivatives*
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Isoleucine / chemistry
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Isoleucine / isolation & purification
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Isoleucine / pharmacology
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Liver / enzymology
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Mice
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Mice, Inbred ICR
Substances
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Cysteine Proteinase Inhibitors
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Epoxy Compounds
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WF 14865A
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WF 14865B
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Isoleucine
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Cathepsins
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Endopeptidases
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Cysteine Endopeptidases
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Cathepsin B
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CTSL protein, human
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Cathepsin L
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Ctsl protein, mouse