WF14865A and B, New Cathepsins B and L Inhibitors Produced by Aphanoascus fulvescens: I. Taxonomy, Production, Purification and Biological Properties

• Published in: Journal of antibiotics 2000/05/25, Vol.53(5), pp.449-458
• Main Authors: OTSUKA, TAKANAO, MURAMATSU, YUKO, NAKANISHI, TOMOKO, HATANAKA, HIROSHI, OKAMOTO, MASANORI, HINO, MOTOHIRO, HASHIMOTO, SEIJI
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, microbial producers, chemotherapic agents, antiseptics, disinfecting agents; Aphanoascus fulvescens; Applied microbiology; Ascomycota - metabolism; Biological and medical sciences; Cathepsin B - antagonists & inhibitors; Cathepsin L; Cathepsins - antagonists & inhibitors; Chromatography, Liquid; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors - classification; Cysteine Proteinase Inhibitors - isolation & purification; Cysteine Proteinase Inhibitors - pharmacology; Endopeptidases; Epoxy Compounds - chemistry; Epoxy Compounds - isolation & purification; Epoxy Compounds - pharmacology; Female; Fundamental and applied biological sciences. Psychology; General aspects; Humans; Isoleucine - analogs & derivatives; Isoleucine - chemistry; Isoleucine - isolation & purification; Isoleucine - pharmacology; Liver - enzymology; Mice; Mice, Inbred ICR; Microbiology; WF14865A; WF14865B
• ISSN: 0021-8820; 1881-1469
• DOI: 10.7164/antibiotics.53.449

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 WF 14865A 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 8.4-72 nM in vitro. Though their in vitro properties were typical as trans-epoxysuccmyl type inhibitors, they exerted strong bone resorption inhibitory effects in low-calcium-diet-fed mouse model at 3.2-10mg/kg.