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

2011 Fiscal Year Final Research Report

• 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 (40510285)
• Project Period (FY): 2009 – 2011
• 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

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 Pages: 629-641
  • DOI: DOI:10.1002/bip.22054.
  • 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 Pages: 111-121
  • DOI: 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 Pages: 595-600
  • DOI: DOI:10.1002/psc.1381
  • 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
  • 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] 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 Pages: 12299-12311
  • DOI: 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] 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
  • Year and Date: 20111021-23
• [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
  • Year and Date: 20100900
• [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
  • Year and Date: 20100604-07