Structure based development of novel specific inhibitors for cathepsin L and cathepsin S in vitro and in vivo.
Specific inhibitors for cathepsin L and cathepsin S have been developed with the help of computer-graphic modeling based on the stereo-structure. The common fragment, N-(L-trans-carbamoyloxyrane-2-carbonyl)-phenylalanine-dimethyla mide, is required for specific inhibition of cathepsin L. Seven novel inhibitors of the cathepsin L inhibitor Katunuma (CLIK) specifically inhibited cathepsin L at a concentration of 10(-7) M in vitro, while almost no inhibition of cathepsins B, C, S and K was observed. Four of the CLIKs are stable, and showed highly selective inhibition for hepatic cathepsin L in vivo. One of the CLIK inhibitors contains an aldehyde group, and specifically inhibits cathepsin S at 10(-7) M in vitro.
Katunuma
N
N
Institute for Health Sciences, Tokushima Bunri University, Japan.
Murata
E
E
Kakegawa
H
H
Matsui
A
A
Tsuzuki
H
H
Tsuge
H
H
Turk
D
D
Turk
V
V
Fukushima
M
M
Tada
Y
Y
Asao
T
T
D000818:Animals; D002219:Carbamates / Q000737:chemistry*; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000187:drug effects; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003196:Computer Graphics; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors; D015195:Drug Design; D010450:Endopeptidases; D006801:Humans; D007421:Intestine, Small / Q000187:drug effects; D007700:Kinetics; D007930:Leucine / Q000031:analogs & derivatives*; D008099:Liver / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects; D051379:Mice; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry*; D051381:Rats; D011994:Recombinant Proteins / Q000187:drug effects; D013154:Spleen / Q000187:drug effects; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013997:Time Factors
D002219:Carbamates; D015853:Cysteine Proteinase Inhibitors; D011994:Recombinant Proteins; D010649:Phenylalanine; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse; C534280:Ctsl protein, rat; C028217:cathepsin S; D007930:Leucine