Research and development of drugs of prevention and treatment for complication of diabetes targeting the receptor of advanced glycation end products(RAGE)

• Project/Area Number: 21390013
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Physical pharmacy
• Research Institution: Osaka University of Pharmaceutical Sciences
• Principal Investigator: KOBAYASHI Yuji 大阪薬科大学, 薬学部, 教授 (20127228)
• Co-Investigator(Kenkyū-buntansha): YAMADA Takashi 大阪薬科大学, 薬学部, 准教授 (20278592) ; NISHIMURA Mitsuhiro 大阪薬科大学, 薬学部, 博士研究員 (40510285)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥19,240,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥4,440,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2010: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2009: ¥13,780,000 (Direct Cost: ¥10,600,000、Indirect Cost: ¥3,180,000)
• Keywords: 創薬 / 糖尿病 / 最終糖化産物 / AGE / RAGE / SBDD / バーチャルスクリーニング / NMR / 合理的薬物設計 / AGE受容体 / AGE-RAGE相互作用 / PPARγ / 等温滴定型熱量計 / 水和 / 終末糖化産物 / 糖尿病合併症 / 分子間相互作用 / 超遠心分析用蛍光測定装置 / 超遠心分析 / 合理的創薬 / 糖尿病血管合併症 / リガンド / レセプター

Research Abstract

The worst three complications of diabetes ; retinopathy, nephritis and neurosis, are due to phenomena in vascular endothelial cells induced by the binding of AGE to its receptor.(AGE ; Advanced Glycation End products, the reaction products between protein and sugar in blood) The aim of this project is to develop therapeutic agents for diabetic vascular complications by rational design and chemical synthesis of candidates to inhibit this interaction with considering the structural information obtained by NMR, X-ray crystallography, conformation energy calculation and thermodynamic information by ultracentrifugation analysis and isothermal titration calorimetry and so on.

Research Products

• [Journal Article] Conformational preferences of 4-chloroproline residues (2012)
  • Author(s): Park HS, Byun BJ, Motooka D, Kawahara K, Doi M, Nakazawa T, Kobayashi Y, Kang YK
  • Journal Title: Biopolymers Volume: 97 Issue: 8 Pages: 629-641
  • DOI: 10.1002/bip.22054
  • Peer Reviewed
• [Journal Article] Polymorphism of Collagen Triple Helix Revealed by (19)F NMR of Mode 1 Peptide [Pro-4(R)-Hydroxyprolyl-Gly](3)-[Pro-4(R)-Fluoroprolyl-Gly]-[Pro-4(R)-Hydroxyprolyl-Gly](3) (2012)
  • Author(s): Kawahara K, Nemoto N, Motooka D, Nishi Y, Doi M, Uchiyama S, Nakazawa T, Nishiuchi Y, Yoshida T, Ohkubo T, Kobayashi Y
  • Journal Title: J Phys Chem B. Volume: 116 Issue: 23 Pages: 6908-6915
  • DOI: 10.1021/jp212631q
  • Peer Reviewed
• [Journal Article] The triple helical structure and stability of collagen model peptide with 4(S)-hydroxyprolyl-pro-gly units (2011)
  • Author(s): Motooka D, Kawahara K, Nakamura S, Doi M, Nishi Y, Nishiuchi Y, Kee Kang Y, Nakazawa T, Uchiyama S, Yoshida T, Ohkubo T, Kobayashi Y
  • Journal Title: Biopolymers Volume: 98 Issue: 2 Pages: 111-121
  • DOI: 10.1002/bip.21730
  • Peer Reviewed
• [Journal Article] Assembly states of the nucleosome assembly protein 1(NAP-1) revealed by sedimentation velocity and non-denaturing MS (2011)
  • Author(s): Noda M, Uchiyama S, McKay AR, Morimoto A, Misawa S, Yoshida A, Shimahara H, Takinowaki H, Nakamura S, Kobayashi Y, Matsunaga S, Ohkubo, T, Robinson CV, Fukui K
  • Journal Title: Biochem. J Volume: 436 Pages: 101-112
  • URL: http://www.biochemj.org/bj/436/0101/bj4360101.htm
  • Peer Reviewed
• [Journal Article] Increasing the hydrolysis constant of the reactive site upon introduction of an engineered Cys14-Cys39 bond into the ovomucoid third domain from silver pheasant (2011)
  • Author(s): Hemmi H, Kumazaki T, Kojima S, Yoshida T., Ohkubo, T, Yokosawa H, Miura K, and Kobayashi Y
  • Journal Title: J. Peptide Science Volume: 8 Issue: 8 Pages: 595-600
  • DOI: 10.1002/psc.1381
  • Peer Reviewed
• [Journal Article] Assembly states of the nucleosome assembly protein 1 (NAP-1) revealed by sedimentation velocity and non-denaturing MS (2011)
  • Author(s): Noda M, Uchiyama S, McKay AR, Morimoto A, Misawa S, Yoshida A, Shimahara H, Takinowaki H, Nakamura S, Kobayashi Y, Matsunaga S, Ohkubo T, Robinson CV, Fukui K
  • Journal Title: Biochem J. Volume: 436 Issue: 1 Pages: 101-112
  • DOI: 10.1042/bj20102063
  • Peer Reviewed
• [Journal Article] Structure and Reaction Mechanism of Human Nicotinamide Phosphoribosyltransferase (2010)
  • Author(s): Takahashi R, Nakamura S, Nakazawa T, Minoura K, Yoshida T, Nishi Y, Kobayashi Y, Ohkubo T
  • Journal Title: J. Biochem Volume: 147 Pages: 95-107
  • NAID: 10027873352
  • URL: http://jb.oxfordjournals.org/content/147/1/95.long
  • Peer Reviewed
• [Journal Article] Structural and dynamic features of the MutT protein in the recognition of nucleotides with the mutagenic 8-oxoguanine base (2010)
  • Author(s): T. Nakamura, S. Meshitsuka, S. Kitagawa, N. Abe, J. Yamada, T. Ishino, H. Nakano, T. Tsuzuki, T. Doi, S. Fujii, Y. Kobayashi, M. Sekiguchi, Y. Yamagata J
  • Journal Title: Biol. Chem Volume: 285 Pages: 444-452
  • URL: http://www.jbc.org/content/285/1/444.long
  • Peer Reviewed
• [Journal Article] Cloming, expression, crystallization and preliminary X-ray crystallographic analysis of a human condensin SMC2 hinge domain with short coiled coils. (2010)
  • Author(s): Y.Kobayashi, et al.
  • Journal Title: Acta Crystallogr Sect F Struct Biol Cryst Commun. Volume: 66 Pages: 1067-1070
  • Peer Reviewed
• [Journal Article] Thermal effects of added propanol on the helix-coil transition of(Pro-Pro-Gly)10 in D2O solution : An NMR study (2010)
  • Author(s): Y.Kobayashi, et al.
  • Journal Title: Chemical Physics Letters Volume: 491 Pages: 208-221
  • Peer Reviewed
• [Journal Article] Characterization of HIV-1 resistance to a fusion inhibitor, N36, derived from the gp41 amino-terminal heptad repeat. (2010)
  • Author(s): Y.Kobayashi, et al.
  • Journal Title: Antiviral Res. Volume: 87 Pages: 179-186
  • Peer Reviewed
• [Journal Article] Structure and reaction mechanism of human nicotinamide phosphoribosyl-transferase. (2010)
  • Author(s): Y.Kobayashi, et al.
  • Journal Title: J Biochem. Volume: 147 Pages: 95-107
  • NAID: 10027873352
  • Peer Reviewed
• [Journal Article] Structural and dynamic features of the MutT protein in the recognition of nucleotides with the mutagenic 8-oxoguanine base. (2010)
  • Author(s): Y.Kobayashi, et al.
  • Journal Title: J Biol Chem. Volume: 285 Pages: 444-452
  • Peer Reviewed
• [Journal Article] Structure-activity relationship of marinostatin, a serine protease inhibitor isolated from a marine organism (2010)
  • Author(s): Y.Kobayashi, et al.
  • Journal Title: J Pept Sci. Volume: 16 Pages: 329-336
  • Peer Reviewed
• [Journal Article] Effect of antibody affinity and antigen valence on molecular forms of immune complexes (2009)
  • Author(s): Oda M, Uchiyama S, Noda M, Nishi Y, Koga M, Mayanagi K, Robinson C. V., Fukui K, Kobayashi Y, Morikawa K, Azuma T
  • Journal Title: Mol. Immunol Volume: 47 Pages: 357-364
  • URL: http://www.sciencedirect.com/science/article/pii/S0161589009007111
  • Peer Reviewed
• [Journal Article] Crystal Structure of Human Ribosomal Protein L10 Core Domain Reveals Eukaryote-Specific Motifs in Addition to the Conserved Fold (2008)
  • Author(s): Nishimura M, Kaminishi T, Takemoto C, Kawazoe M, Yoshida T, Tanaka A, Sugano S, Shirouzu M, Ohkubo T, Yokoyama S, Kobayashi Y
  • Journal Title: J Mol Biol Volume: 377 Pages: 421-430
  • URL: http://www.sciencedirect.com/science/article/pii/S002228360800020X
  • Peer Reviewed
• [Journal Article] The Solution Structure of Variable-type Domain of Receptor for Advanced Glycation Endproducts : Identification of the AGE-binding Site (2008)
  • Author(s): S. Matsumoto, T. Yoshida, H. Murata, S. Nakamura, Y. Yamamoto, T. Watanabe, H. Yonekura, H. Yamamoto, T. Ohkubo and Y. Kobayashi
  • Journal Title: Biochemistry Volume: 47 Issue: 47 Pages: 12299-12311
  • DOI: 10.1021/bi800910v
  • Peer Reviewed
• [Journal Article] Polymorphism of Collagen Triple Helix Revealed by(19) F NMR of Model Peptide [Pro-4(R)-Hydroxyprolyl-Gly](3)-[Pro-4(R)-Fluoroprolyl-Gly]-[Pro-4(R)-Hydroxyprolyl-Gly](3)
  • Author(s): Kawahara K, Nemoto N, Motooka D, Nishi Y, Doi M, Uchiyama S, Nakazawa T, Nishiuchi Y, Yoshida T, Ohkubo T, Kobayashi Y
  • Journal Title: J Phys Chem B Volume: (in press)
  • Peer Reviewed
• [Presentation] 絹蛋白質の物理化学的基礎 (2011)
  • Author(s): 小林祐次
  • Organizer: 奈良女子大学古代史・環境史プロテオミクス研究創成事業本部主催シンポジウム
  • Place of Presentation: 奈良県奈良市
  • Year and Date: 2011-11-12
• [Presentation] 合理的創薬を目指した構造解析と熱力学的解析 (2011)
  • Author(s): 小林祐次
  • Organizer: 第47回熱測定討論会
  • Place of Presentation: 群馬県桐生市
• [Presentation] 立体構造情報を用いた終末糖化産物AGE受容体とHMGB1間の相互作用解析 (2010)
  • Author(s): 小林祐次, 他
  • Organizer: 日本結晶学会年会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-08
• [Presentation] 炭酸脱水酵素の触媒反応におけるプロトントランスファの量子化学的解析のためのモデル-互変異性が変化する状態にあるHis64のスウィング運動の関与について (2010)
  • Author(s): 小林祐次, 他
  • Organizer: 日本結晶学会年会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-07
• [Presentation] 毒素原性大腸菌の線毛形成蛋白質CofAの結晶化 (2010)
  • Author(s): 小林祐次、西村光広, 他
  • Organizer: 日本結晶学会年会
  • Place of Presentation: 大阪
  • Year and Date: 2010-12-05
• [Presentation] Thermodynamic and structural analysis of PPARγ-ligand interaction (2010)
  • Author(s): M.Nishimura, Y Kobayashi
  • Organizer: 5th International Peptide Symposium in conjyunction with 47th Japanese Peptide Symposium
  • Place of Presentation: 京都
  • Year and Date: 2010-12-05
• [Presentation] Inter-molecular Interactions between Adiponectin and AdipoRs (2010)
  • Author(s): Y.Kobayashi, et al.
  • Organizer: 5th International Peptide Symposium in conjyunction with 47th Japanese Peptide Symposium
  • Place of Presentation: 京都
  • Year and Date: 2010-12-05
• [Presentation] The Crystal Structure of the Collagen Model Peptide containing 4(S)-hydroxyproline-proline-glycine Repeats (2010)
  • Author(s): Y.Kobayashi, et al.
  • Organizer: 5th International Peptide Symposium in conjyunction with 47th Japanese Peptide Symposium
  • Place of Presentation: 京都
  • Year and Date: 2010-12-05
• [Presentation] Identification of conformational heterogeneity of Collagen Model Peptide by19 F-NMR (2010)
  • Author(s): Y.Kobayashi, et al.
  • Organizer: 5th International Peptide Symposium in conjyunction with 47th Japanese Peptide Symposium
  • Place of Presentation: 京都
  • Year and Date: 2010-12-05
• [Presentation] 終末糖化産物受容体(RAGE)リガンド結合領域の結晶化 (2010)
  • Author(s): 鬼頭万里子、小林祐次, 他
  • Organizer: 日本結晶学会年会
  • Place of Presentation: 大阪
  • Year and Date: 2010-12-04
• [Presentation] PPARγ-LBD/FK-614複合体のX線結晶構造解析 (2010)
  • Author(s): 小林祐次, 他
  • Organizer: 日本結晶学会年会
  • Place of Presentation: 大阪
  • Year and Date: 2010-12-03
• [Presentation] 分子動力学法によるコンデンシンヒンジドメインの構造解析 (2010)
  • Author(s): 小林祐次, 他
  • Organizer: 第24回 分子シミュレーション討論会
  • Place of Presentation: 福井
  • Year and Date: 2010-11-24
• [Presentation] C 型肝炎ウイルス(HCV)のコア蛋白質とヒト プロテアソーム活性化因子PA28γの相互作用をターゲットとしたC型肝炎治療薬の探索 (2010)
  • Author(s): 小林祐次, 他
  • Organizer: 日本薬学会近畿支部大会
  • Place of Presentation: 大阪
  • Year and Date: 2010-10-30
• [Presentation] 真正細菌由来シャペロンとその阻害分子の相互作用解析 (2010)
  • Author(s): 小林祐次, 他
  • Organizer: 日本薬学会近畿支部大会
  • Place of Presentation: 大阪
  • Year and Date: 2010-10-30
• [Presentation] リポカリン型プロスタグランジンD合成酵素の酵素反応機構の解明 (2010)
  • Author(s): 小林祐次, 他
  • Organizer: 日本薬学会近畿支部大会
  • Place of Presentation: 大阪
  • Year and Date: 2010-10-30
• [Presentation] PPARγ-リガンド複合体の分子間相互作用解析 (2010)
  • Author(s): 西村光広、小林祐次, 他
  • Organizer: 熱測定学会
  • Place of Presentation: 三重
  • Year and Date: 2010-09-27
• [Presentation] Structural and thermodynamic analyses on complex of PPARγ and its ligand (2010)
  • Author(s): Y.Kobayashi
  • Organizer: The 13th Akabori Conference : German-Japanese Symposium on Peptide Science
  • Place of Presentation: ドイツ
  • Year and Date: 2010-09-01
• [Presentation] PPARγ-リガンド複合体の結晶構造解析及び熱力学的相互作用解析 (2010)
  • Author(s): 西村光広、小林祐次, 他
  • Organizer: Biophysical Interaction Analysis symposium 2010
  • Place of Presentation: 東京
  • Year and Date: 2010-07-16
• [Presentation] 病原性大腸菌腸管付着因子CofJのX 線結晶構造解析 (2010)
  • Author(s): 小林祐次, 他
  • Organizer: 蛋白質科学会年会
  • Place of Presentation: 北海道
  • Year and Date: 2010-06-17
• [Presentation] リポカリン型プロスタグランジンD合成酵素の基質認識機構 (2010)
  • Author(s): 小林祐次, 他
  • Organizer: 蛋白質科学会年会
  • Place of Presentation: 北海道
  • Year and Date: 2010-06-16
• [Presentation] Molecular interaction of PPARγ with its ligand (2010)
  • Author(s): Y.Kobayashi
  • Organizer: 12th Naples Workshop on Bioactive Peptides
  • Place of Presentation: イタリア
  • Year and Date: 2010-06-06
• [Presentation] 立体構造に基づく終末糖化産物AGE受容体とリガンド間の相互作用解析 (2010)
  • Author(s): 小林祐次
  • Organizer: 第57回日本生化学会近畿支部例会
  • Place of Presentation: 奈良
  • Year and Date: 2010-05-22
• [Presentation] リポカリン型プロスタグランジンD合成酵素の立体構造決定とリガンド認識様式の解明 (2010)
  • Author(s): 小林祐次, 他
  • Organizer: 第57回日本生化学会近畿支部例会
  • Place of Presentation: 奈良
  • Year and Date: 2010-05-22
• [Presentation] Structural insights into the activation of PPARγ by organotin compounds (2010)
  • Author(s): Y.Kobayashi
  • Organizer: The 5th Seoul-Kyoto-Osaka Joint Symposium on Pharmaceutical Sciences for Young Scientists
  • Place of Presentation: 大阪
  • Year and Date: 2010-05-19
• [Presentation] 立体構造に基づく終末糖化産物AGE受容体とリガンド間の相互作用解析 (2010)
  • Author(s): 藤田直子, 小林祐次, ほか
  • Organizer: 日本薬学会 第130回年会
  • Place of Presentation: 岡山
  • Year and Date: 2010-03-29
• [Presentation] Molecular interaction of PPAR□with its ligand (2010)
  • Author(s): 小林祐次
  • Organizer: 12th Naples Workshop on Bioactive Peptides
  • Place of Presentation: イタリア
• [Presentation] Structural and thermodynamic analyses on complex of PPAR γ and its ligand (2010)
  • Author(s): 小林祐次
  • Organizer: The 13th Akabori Conference : German-Japanese Symposium on Peptide Science
  • Place of Presentation: ドイツ
• [Presentation] 構造情報に基づく合理的薬剤設計―RAGEアンタゴニスト薬の探索 (2009)
  • Author(s): 小林祐次, ほか
  • Organizer: 第19回日本メイラード学会
  • Place of Presentation: 金沢
  • Year and Date: 2009-11-20
• [Presentation] 合理的薬物設計を目指したタンパク質の構造と相互作用解析 (2009)
  • Author(s): 小林祐次
  • Organizer: ハイペップ研究所沖縄国際ワークショップ
  • Place of Presentation: 沖縄県うるま市
  • Year and Date: 2009-07-20