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Featured researches published by Tetsuji Asao.


FEBS Letters | 1999

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

Nobuhiko Katunuma; Etsuko Murata; Hisao Kakegawa; A. Matsui; H. Tsuzuki; Hideaki Tsuge; Dušan Turk; Vito Turk; M. Fukushima; Yukio Tada; Tetsuji Asao

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.


Immunology | 2000

Lysosomal cathepsin B plays an important role in antigen processing, while cathepsin D is involved in degradation of the invariant chain in ovalbumin-immunized mice

Tianqian Zhang; Yoichi Maekawa; J. Hanba; T. Dainichi; Baher Fawzy Nashed; Hajime Hisaeda; Tohru Sakai; Tetsuji Asao; Kunisuke Himeno; Robert A. Good; Nobuhiko Katunuma

We previously reported that CA074, a specific inhibitor of cathepsin B, modulates specific immune responses from the T helper 2 (Th2) type to Th1 type in BALB/c mice infected with Leishmania major. In the present study, we found that a similar type of immune deviation was also induced in mice immunized with ovalbumin (OVA). However, treatment of mice with pepstatin A, a specific cathepsin D inhibitor, suppressed the OVA‐specific proliferation of lymphocytes and blocked the development of both Th1 and Th2 cellular responses. These inhibitors did not appear to have any direct influence in vitro on functions of naive lymphocytes. OVA antigen (47 000 MW) was digested mainly into 40 000 MW protein in vitro by lysosomal proteases from naive BALB/c mice, and its digestion was markedly inhibited by the addition of CA074, but not by addition of pepstatin A, during incubation. However, pepstatin A strongly suppressed the degradation of the major histocompatibility complex class II‐associated invariant chain (Ii) molecule in vivo and in vitro. Thus, cathepsin B appears to process antigens directed to preferential activation of Th2 cells, while cathepsin D may be responsible for the degradation of Ii, the processing of which is essential in initiating the antigen‐specific activation of Th1 and Th2 CD4+ T cells. These lysosomal proteases may have different functions in regulating immune responses.


Advances in Enzyme Regulation | 1999

Study of the functional share of lysosomal cathepsins by the development of specific inhibitors.

Nobuhiko Katunuma; A. Matsui; T Kakegawa; Etsuko Murata; Tetsuji Asao; Yasuo Ohba

To analyze the functional share of individual cathepsins, we developed powerful and specific inhibitors for individual cathepsins using computer graphics of substrate binding pockets based on X-ray crystallography. These new inhibitors were named CLIK group. Epoxy succinate peptide derivatives, CLIK-066, 088, 112, 121, 148, 181, 185 and 187, are typical specific inhibitors for cathepsin L. Aldehyde derivatives CLIK-060 and CLIK-164 showed specific inhibition against cathepsin S and cathepsin K, respectively. We found that pyridoxal phosphate (PLP), a coenzyme form of vitamin B6, inhibits all cathepsins and also new artificially synthesized pyridoxal derivatives, CLIK-071 and -072, in which the phosphate esters of PLP were replaced by propionic acid, exhibited strong inhibition for cathepsins. Furthermore, CLIK-071 was easy to incorporate into cells and showed powerful inhibition for intracellular cathepsins. Using these selective inhibitors, the allotment of individual cathepsin functions in cells has been studied as follows. Cathepsin L and/or K participate in bone resorption based on bone type-1 collagen degradation and the L-type protease inhibitors suppressed the bone resorption. Cathepsins B and S participate in antigen presentations based on antigen processing and invariant chain degradation, respectively. Also cathepsin L participates in cell apoptosis mediated by caspase III activation.


Journal of Immunology | 1998

Switch of CD4+ T cell differentiation from Th2 to Th1 by treatment with cathepsin B inhibitor in experimental leishmaniasis.

Yoichi Maekawa; Kunisuke Himeno; Hiroyuki Ishikawa; Hajime Hisaeda; Tohru Sakai; Teruki Dainichi; Tetsuji Asao; Robert A. Good; Nobuhiko Katunuma


Biochemical and Biophysical Research Communications | 1999

Inhibition mechanism of cathepsin L-specific inhibitors based on the crystal structure of papain-CLIK148 complex.

Hideaki Tsuge; Tomohiro Nishimura; Yukio Tada; Tetsuji Asao; Dušan Turk; Vito Turk; Nobuhiko Katunuma


Biochemical and Biophysical Research Communications | 2000

Structure-based development of pyridoxal propionate derivatives as specific inhibitors of cathepsin K in vitro and in vivo.

Nobuhiko Katunuma; A. Matsui; Tomoko Inubushi; Etsuko Murata; Hisao Kakegawa; Y. Ohba; Dušan Turk; Vito Turk; Yukio Tada; Tetsuji Asao


Archives of Biochemistry and Biophysics | 2002

Structure-based design of specific cathepsin inhibitors and their application to protection of bone metastases of cancer cells.

Nobuhiko Katunuma; Hideaki Tsuge; M. Nukatsuka; Tetsuji Asao; M. Fukushima


International Immunology | 2001

Treatment with cathepsin L inhibitor potentiates Th2-type immune response in Leishmania major-infected BALB/c mice.

Tianqian Zhang; Yoichi Maekawa; Tohru Sakai; Yoko Nakano; Kazunari Ishii; Hajime Hisaeda; Teruki Dainichi; Tetsuji Asao; Nobuhiko Katunuma; Kunisuke Himeno


Biochemical and Biophysical Research Communications | 2000

Pepstatin A-Sensitive Aspartic Proteases in Lysosome Are Involved in Degradation of the Invariant Chain and Antigen-Processing in Antigen Presenting Cells of Mice Infected with Leishmania major☆☆☆

Tianqian Zhang; Yoichi Maekawa; Koji Yasutomo; Hiroyuki Ishikawa; Baher Fawzy Nashed; T. Dainichi; Hajime Hisaeda; Tohru Sakai; Michiyuki Kasai; Toshiaki Mizuochi; Tetsuji Asao; Nobuhiko Katunuma; Kunisuke Himeno


Biochemical and Biophysical Research Communications | 2001

Splenic Cathepsin L Is Maturated from the Proform by Interferon-γ after Immunization with Exogenous Antigens

Tianqian Zhang; Yoichi Maekawa; Tohru Sakai; Yoko Nakano; Kazunari Ishii; Hajime Hisaeda; Eiki Kominami; Nobuhiko Katunuma; Tetsuji Asao; Kunisuke Himeno

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Nobuhiko Katunuma

Tokushima Bunri University

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A. Matsui

Tokushima Bunri University

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Tohru Sakai

University of Tokushima

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Etsuko Murata

Tokushima Bunri University

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