Structure based development of novel specific inhibitors for cathepsin L and cathepsin S in vitro and in vivo

FEBS Letters

Asao, T.²  Katunuma, N.³  Tsuzuki, H.³  Turk, D.¹  Matsui, A.³  Tsuge, H.³  Kakegawa, H.³  Fukushima, M.²  Turk, V.¹  Murata, E.³  Tada, Y.² 

[1] Department of Biochemistry, J. Stefan Institute, Jamova, Ljubliana, Slovenia;Research Institute for New Drug Design, Taiho Pharmaceutical Company, Hanno, Japan;Institute for Health Sciences, Tokushima Bunri University, Yamasirocho, Tokushima 770-8514, Japan

关键词: Cathepsin L;    Cathepsin S;    Cathepsin inhibitor;    Epoxysuccinate;    X-ray crystallography;    E-64;    1-[L-N-(trans-epoxysuccinyl) leucyl] amino-4-guanidinobutane;    CA-030;    ethyl-ester of epoxysuccinyl-L-isoleucyl-L-proline;    CA-074;    propyl-amide of epoxysuccinyl-L-isoleucyl-L-proline;    MCA;    methyl coumaryl amide;    CLIK;    cathepsin L inhibitor Katunuma;    MS;    mass spectroscopy;    IR;    infrared spectroscopy;    NMR;    nuclear magnetic resonance spectroscopy;    KPB;    potassium phosphate buffer;    HPLC;    high performance liquid chromatography;   

DOI  :  10.1016/S0014-5793(99)01107-2

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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-dimethylamide, 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.

【 授权许可】

Unknown