WF14865A and B, new cathepsins B and L inhibitors produced by Aphanoascus fulvescens. I. Taxonomy, production, purification and biological properties.
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.
Otsuka
T
T
Exploratory Research Laboratories, Fujisawa Pharmaceutical Co, Ltd, Tsukuba, Ibaraki, Japan.
Muramatsu
Y
Y
Nakanishi
T
T
Hatanaka
H
H
Okamoto
M
M
Hino
M
M
Hashimoto
S
S
D000818:Animals; D001203:Ascomycota / Q000378:metabolism*; D002401:Cathepsin B / Q000037:antagonists & inhibitors*; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D002853:Chromatography, Liquid; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000145:classification* / Q000302:isolation & purification / Q000494:pharmacology; D010450:Endopeptidases; D004852:Epoxy Compounds / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D005260:Female; D006801:Humans; D007532:Isoleucine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D008099:Liver / Q000201:enzymology; D051379:Mice; D008813:Mice, Inbred ICR
D015853:Cysteine Proteinase Inhibitors; D004852:Epoxy Compounds; C411673:WF 14865A; C411674:WF 14865B; D007532:Isoleucine; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse