Faculty Profiles - Tanaka Tomohiro

Peptide HIV-1 integrase inhibitors from HIV-1 gene products. Reviewed

Suzuki S, Urano E, Hashimoto C, Tsutsumi H, Nakahara T, Tanaka T, Nakanishi Y, Maddali K, Han Y, Hamatake M, Miyauchi K, Pommier Y, Beutler JA, Sugiura W, Fuji H, Hoshino T, Itotani K, Nomura W, Narumi T, Yamamoto N, Komano JA, Tamamura H

Journal of medicinal chemistry 53 ( 14 ) 5356 - 5360 2010.7

Remodeling of Dynamic Structures of HIV-1 Envelope Proteins Leads to Synthetic Antigen Molecules Inducing Neutralizing Antibodies Reviewed

Toru Nakahara, Wataru Nomura, Kenji Ohba, Aki Ohya, Tomohiro Tanaka, Chie Hashimoto, Tetsuo Narumi, Tsutomu Murakami, Naoki Yamamoto, Hirokazu Tamamura

BIOCONJUGATE CHEMISTRY 21 ( 4 ) 709 - 714 2010.4

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER CHEMICAL SOC

A synthetic antigen targeting membrane-fusion mechanism of HIV-1 has a newly designed template with C3-symmetric linkers mimicking N36 trimeric form. The antiserum produced by immunization of the N36 trimeric form antigen showed structural preference in binding to N36 trimer and stronger inhibitory activity against HIV-1 infection than the N36 monomer. Our results suggest an effective strategy of HIV vaccine design based on a relationship to the native structure of proteins involved in HIV fusion mechanisms.

DOI： 10.1021/bc900502z

Stereoselective synthesis of peptidomimetics based on acid-catalyzed ring-opening of beta-aziridinyl-alpha,beta-enoates. Reviewed

エイズワクチンを指向した宿主受容体CXCR4由来抗原分子の創製 Reviewed

橋本知恵, 野村渉, 田中智博, 中原徹, 鳴海哲夫, 大庭賢二, 村上努, 山本直樹, 玉村啓和

日本薬学会年会要旨集 130年会 ( 2 ) 71 - 71 2010.3

合成抗原ペプチドによるHIV-1 gp41の三量体構造を認識する抗体の誘導 Reviewed

野村渉, 中原徹, 大矢亜紀, 大庭賢二, 田中智博, 橋本知恵, 鳴海哲夫, 村上努, 山本直樹, 玉村啓和

日本薬学会年会要旨集 130年会 ( 2 ) 114 - 114 2010.3

CD4 mimics targeting the mechanism of HIV entry. Reviewed

Yamada Y, Ochiai C, Yoshimura K, Tanaka T, Ohashi N, Narumi T, Nomura W, Harada S, Matsushita S, Tamamura H

Bioorganic & medicinal chemistry letters 20 ( 1 ) 354 - 358 2010.1

Beyond antibodyという研究領域ペプチドミメティクを基盤とした阻害剤と新規概念によるワクチン Reviewed

玉村啓和, 野村渉, 鳴海哲夫, 田中智博, 駒野淳, 山本直樹

日本生化学会大会プログラム・講演要旨集 82回 1S4a - 4 2009.9

センシングバイオロジーを指向した蛍光性CXCR4プローブの創出とリガンドスクリーニング法の開発 Reviewed

堤浩, 野村渉, 田中智博, 田部泰章, 糸谷恭子, 玉村啓和

生体材料工学研究所年報 42 3 - 7 2009.3

Fluorogenically Active Leucine Zipper Peptides as Tag-Probe Pairs for Protein Imaging in Living Cells Reviewed

Hiroshi Tsutsumi, Wataru Nomura, Seiichiro Abe, Tomoaki Mino, Akemi Masuda, Nami Ohashi, Tomohiro Tanaka, Kenji Ohba, Naoki Yamamoto, Kazunari Akiyoshi, Hirokazu Tamamura

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION 48 ( 48 ) 9164 - 9166 2009

Development of chemokine receptor CXCR4 antagonists using bio-mimetic strategy. Reviewed

Tamamura H, Tanaka T, Tsutsumi H, Ohashi N, Hiramatsu K, Araki T, Ojida A, Hamachi I, Wang Z, Peiper SC, Trent JO, Ueda S, Oishi S, Fujii N

Advances in experimental medicine and biology 611 145 - 146 2009

Tamamura H, Tanaka T, Tsutsumi H, Nemoto K, Mizokami S, Ohashi N, Oishi S, Fujii N

Advances in experimental medicine and biology 611 149 - 150 2009

Structure-activity relationship study on artificial CXCR4 ligands possessing the cyclic pentapeptide scaffold: the exploration of amino acid residues of pentapeptides by substitutions of several aromatic amino acids Reviewed

Tomohiro Tanaka, Wataru Nomura, Tetsuo Narumi, Ai Esaka, Shinya Oishi, Nami Ohashi, Kyoko Itotani, Barry J. Evans, Zi-xuan Wang, Stephen C. Peiper, Nobutaka Fujii, Hirokazu Tamamura

ORGANIC & BIOMOLECULAR CHEMISTRY 7 ( 18 ) 3805 - 3809 2009

Language：English Publishing type：Research paper (scientific journal) Publisher：ROYAL SOC CHEMISTRY

Previously, downsizing of a 14-residue peptidic CXCR4 antagonist 1 has led to the development of a highly potent CXCR4 antagonist 2 [cyclo(-D-Tyr(1)-Arg(2)-Arg(3)-Nal(4)-Gly(5)-)]. In the present study, cyclic pentapeptide libraries that were designed by substitutions of several amino acids for D-Tyr(1) and Arg(2) in peptide 2 were prepared and screened to evaluate binding activity for CXCR4. The above structure-activity relationship study led to the finding of several potent CXCR4 ligands.

DOI： 10.1039/b908286g

A future perspective on the development of chemokine receptor CXCR4 antagonists Reviewed

Hirokazu Tamamura, Hiroshi Tsutsumi, Wataru Nomura, Tomohiro Tanaka, Nobutaka Fujii

EXPERT OPINION ON DRUG DISCOVERY 3 ( 10 ) 1155 - 1166 2008.10

Language：English Publisher：INFORMA HEALTHCARE

Background: In the postgenome era, G-protein-coupled receptor families have been recognized as significant drug targets in medicinal chemistry. A specific chemokine receptor, CXCR4, has multiple critical functions in normal physiologies including embryonic development of the cardiovascular, hemopoietic and central nervous systems, and underlies problematic pathologies such as HIV infection, cancer metastasis, leukemia progression and rheumatoid arthritis. Methods and results: A tetradecamer peptide, T140, derived from the horseshoe crab, and its biologically stable derivative, 4F-benzoyl-TN14003, were found to be powerful CXCR4 antagonists that block HIV entry to cells. These peptides have also shown remarkable inhibitory activity against cancer metastasis and progression in a variety of cancers. Slow release administration of 4F-benzoyl-TN14003, for example, was found to significantly reduce pulmonary metastasis of breast cancer cells in severe combined immunodeficient mice. This peptide also shows inhibitory effects against melanoma metastasis and Epstein-Barr virus-associated lymphoproliferation in mice, suppresses the delayed-type hypersensitivity response induced by sheep red blood cells and reduced collagen-induced arthritis in both mouse models of arthritis. Conclusion: T140 analogues have the potential to become promising agents for chemotherapy of AIDS, cancer and rheumatoid arthritis. This review summarizes the development of low molecular weight CXCR4 antagonists based on pharmacophore identification in T140 analogues and also provides an opinion on the future of the development of CXCR4 antagonists.

DOI： 10.1517/17460440802373379

Fluorophore labeling enables imaging and evaluation of specific CXCR4-ligand interaction at the cell membrane for fluorescence-based screening Reviewed

Wataru Nomura, Yasuaki Tanabe, Hiroshi Tsutsumi, Tomohiro Tanaka, Kenji Ohba, Naoki Yamamoto, Hirokazu Tamamura

BIOCONJUGATE CHEMISTRY 19 ( 9 ) 1917 - 1920 2008.9

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER CHEMICAL SOC

Development of CXCR4-specific ligands is an important issue in chemotherapy of HIV infection, cancer metastasis, and rheumatoid arthritis, and numerous potential ligands have been developed to date. However, it is difficult to assess their binding mode and specificity because of uncertainties in the structure of the CXCR4-ligand complexes. To address this problem, we have synthesized fluorophore labeled Ac-TZ14011, which is derived from T140, a powerful CXCR4 antagonist. Binding of Ac-TZ14011 to CXCR4 on the cell membrane was observed by fluorescence microscope, and analysis of the binding data produced IC50 values of several ligands comparable to those obtained in RI-based assays. This fluorescence-based assay is applicable to explore new pharmacophores of CXCR4-specific ligands with high-throughput screening and also to screening of the other GPCR binding ligands.

DOI： 10.1021/bc800216p

HIV侵入の動的超分子機構を標的としたCD4 mimic small moleculeの創製 Reviewed

山田裕子, 吉村和久, 田中智博, 堤浩, 野村渉, 糸谷恭子, 増野弘幸, 柴田潤二, 畑田万紀子, 松下修三, 玉村啓和

日本薬学会年会要旨集 128年会 ( 2 ) 84 - 84 2008.3

Structure-activity relationship study of CXCR4 antagonists bearing the cyclic pentapeptide scaffold: identification of the new pharmacophore Reviewed

Tomohiro Tanaka, Hiroshi Tsutsumi, Wataru Nomura, Yasuaki Tanabe, Nami Ohashi, Ai Esaka, Chihiro Ochiai, Jun Sato, Kyoko Itotani, Tsutomu Murakami, Kenji Ohba, Naoki Yamamoto, Nobutaka Fujii, Hirokazu Tamamura

ORGANIC & BIOMOLECULAR CHEMISTRY 6 ( 23 ) 4374 - 4377 2008

Language：English Publishing type：Research paper (scientific journal) Publisher：ROYAL SOC CHEMISTRY

A highly potent CXCR4 antagonist 2 [cyclo (-D-Tyr(1)-Arg(2)-Arg(3)-Nal(4)-Gly(5)-)] has previously been identified by screening cyclic pentapeptide libraries that were designed based on pharmacophore residues of a 14-residue peptidic CXCR4 antagonist 1. In the present study, D-Tyr and Arg in peptide 2 were replaced by a bicyclic aromatic amino acid and a cationic amino acid, respectively, and their binding activity for CXCR4 was evaluated for identification of the novel pharmacophore.

DOI： 10.1039/b812029c

Versatile use of acid-catalyzed ring-opening of beta-aziridinyl-alpha,beta-enoates to stereoselective synthesis of peptidomimetics Reviewed

Hirokazu Tamamura, Tomohiro Tanaka, Hiroshi Tsutsumi, Koji Nemoto, Satoko Mizokami, Nami Ohashi, Shinya Oishi, Nobutaka Fujii

TETRAHEDRON 63 ( 37 ) 9243 - 9254 2007.9

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Treatment of N-arylsulfonylaziridines bearing alpha,beta-unsaturated esters with alcohols, thiols or weak acids such as AcOH in the presence of catalytic amount of Lewis acids affords regio- and stereoselectively ring-opened products, such as delta-aminated gamma-alkoxy-(alkylthio or acetoxy)-alpha,beta-enoates. In addition, the regio- and stereoselective ring-opening reactions can be performed on solid supports and applied to stereoselective synthesis of (E)-alkene dipeptide isosteres. (C) 2007 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tet.2007.06.029

Therapeutic potential of the chemokine receptor CXCR4 antagonists as multifunctional agents Invited Reviewed

Hiroshi Tsutsumi, Tomohiro Tanaka, Nami Ohashi, Hiroyuki Masuno, Hirokazu Tamamura, Kenichi Hiramatsu, Takanobu Araki, Satoshi Ueda, Shinya Oishi, Nobutaka Fujii

BIOPOLYMERS 88 ( 2 ) 279 - 289 2007

Language：English Publishing type：Research paper (scientific journal) Publisher：JOHN WILEY & SONS INC

The chemokine receptor CXCR4 possesses multiple critical functions in normal and pathological physiology. CXCR4 is a G-protein-coupled receptor that transduces signals of its endogenous ligand, the chemokine CXC12 (stromal cell-derived factor-1, SDF-1). The interaction between CXC12 and CXCR4 plays an important role in the migration of progenitors during embryologic development of the cardiovascular, hemopoietic, central nervous systems, and so on. This interaction is also known to be involved in several intractable disease processes, including HIV infection, cancer cell metastasis, leukemia cell progression, rheumatoid arthritis (RA), and pulmonary fibrosis. It is conjectured that this interaction may be a critical therapeutical target in all of these diseases, and several CXCR4 antagonists have been proposed as potential drugs. Fourteen-mer peptides, T140 and its analogues, were previously developed in our laboratory as specific CXCR4 antagonists that were identified as HIV-entry inhibitors, anti-cancer-metastatic agents, anti-chronic lymphotic/acute lymphoblastic leukemia agents, and anti-RA agents. Cyclic pentapeptides, such as FC131 [cyclo(D-Tyr-Arg-Arg-L-3-(2-naphthyl)alanine-Gly)], were also previously found as CXCR4 antagonist leads based on pharmacophores of T140. This review article describes the elucidation of multiple functions of CXCR4 antagonists and the development of a number of low-molecular weight CXCR4 antagonists involving FC131 analogues and other compounds with different scaffolds including linear-type structures. (c) 2006 Wiley Periodicals, Inc.

DOI： 10.1002/bip.20653