Yasuyuki Igarashi, Kenji Monde, Hiroshi Kida, Shin-Ichiro Nishimura, Susumu Ishida, Satoshi Shuto,
Akio Kihara, Yasuyuki Fujita, Hirofumi Sawa, Satoshi Ichikawa, Yasuro Shinohara, Kousuke Noda,
Hiroshi Hinou, Takayuki Sassa, Masatoshi Okamatsu, Yasuhito Onodera, Yasuko Orba, Atsuhiro Kanda,
Tohru Taniguchi, Yusuke Ohno, Yuta Murai, Junichi Furukawa, Kohei Yuyama, Shota Sakai,
Hamman Mostafa, Hisatoshi Hanamatsu, Artigas Sole Gerard, (Susumu Mitsutake)
[Shionogi & Co., Ltd.]
Takeshi Shiota, Yoshinori Yamano, Masashi Deguchi, Yoshito Numata, Kenichi Higashino, Yutaka Yoshida,
Shoichi Naito, Takeshi Yoshioka, Kouhei Matsui, Akira Naito, Minoru Hasegawa, Hiroshi Takemoto,
Hideo Yukioka, Michitaka Shichijo, Akira Ino, Kazuhiko Maekawa, Akihiko Sato
[Sumitomo Bakelite Co., Ltd.]
Kazuhiko Fujiwara, Akiko Okubo, Mituo Hayashi, Takahiro Katayama
Aiming to establish a drug discovery infrastructure enabling the continual generation of drug candidates, a series of researches to realize efficient design, synthesis of target molecules (from low-molecular-weight compounds to glycosylated proteins) and to serve the objectives of the discovery of novel biomarkers useful in the field of regenerative medicine.
Major subjects are 1) Drug discovery based on sphingolipid /glycosphingolipid functions 2) Comprehensive glycomics as a framework for molecular characterization of cellular state 3) Development of efficient design and synthetic method of glycosylated protein/peptides.
1) Drug discovery based on sphingolipid/glycosphingolipid functions
Sphingolipids/glycosphingolipids are fundamental components of cellular membranes in eukaryotic cells. They are highly bioactive as the essential structures of membrane microdomain and lipid mediators. Furthermore, their metabolic impairments involving in the pathogenesis of several disorders are recently indicated. In this project, we focus on studying about sphingolipid/glycosphingolipid functions and, based on these findings, further apply the achievement to the drug discovery.
Recently, we found that deficiency of sphingomyelin (SM) synthase had resistance to diet-induced obesity. SM has an important role in formation of "metabolic platform" in which various receptors and metabolic enzymes get together. Another, we discovered that SM metabolism modulates release of neuronal exosomes and the vesicles are involved in the formation of Alzheimer's amyloid. Regulation of SM metabolism would be a new approach toward pharmacological therapies against metabolic syndrome and the neurodegenerative disease.
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2) Comprehensive glycomics as a framework for molecular characterization of cellular state
A number of carbohydrate-related biomarkers have been reported to possibly correspond to distinct cellular states such as differentiation, proliferation, or to cell types. Evaluation of cellular states based on comprehensive glycomics is expected to further accelerate the progress. Based on comprehensive glycomics which focuses on all major classes of complex carbohydrates (i.e., glycoproteins, glycolipids, glycosaminoglycans), and subsequent glycoform-focused proteomics/ lipidomics, we seek to discover novel biomarkers suitable for the evaluation, classification, identification and isolation of target cells (e.g., stem cells and their differentiated cells) and for the drug discovery research as well as to establish novel cellular manufacturing techniques in the field of regenerative medicine.
3) Development of efficient design and synthetic method of glycosylated protein/peptides
Our research aim is to discover novel biomarker candidates based on autoantibody by the rapid screening of normal healthy and disease patient serum. To get our goal, we are engaged on three main research elements: At first, construction of glycopeptide libraries by synergy of combinatorial chemistry and enzymatic approach. Secondly, our group established high-throughput assay system using glycopeptide microarray in cooperation with Sumitomo Bakelite. The third element is the study of the binding mode between glycopeptide epitope and antibody by STD-NMR experiments. In terms of NMR study, we are in collaboration with Jimenez-Barbero group（CSIC）, one of the leading groups in the NMR study of interaction between carbohydrates and proteins. We have confirmed adequate performance of glycan and glycopeptide array as screening tool by functional assessment using commercial lectins and antibodies. Currently, we have been engaged on glycan screening using infectious organisms and human serum as well as biomarker discovery research as practical applications of our arrays. In addition, glycan array, part of our effort, was commercialized in Sumitomo bakelite Co., Ltd. last year.