Faculty Profiles - Tanaka Tomohiro

Expressed protein ligation at methionine: N-terminal attachment of homocysteine, ligation, and masking. International journal

Tomohiro Tanaka, Anne M Wagner, John B Warner, Yanxin J Wang, E James Petersson

Angewandte Chemie (International ed. in English) 52 ( 24 ) 6210 - 3 2013.6

Biological Effects of Bivalent-type CXCR4 Ligands with Rigid Linkers Reviewed

Nomura W, Tanaka T, Aoki T, Narumi T, Tamamura H

BIOPOLYMERS 100 ( 3 ) 296 - 296 2013.5

腫瘍認識プローブ・HIV阻害剤としてのケモカイン受容体リガンド Reviewed

野村渉, 田中智博, 大橋南美, 玉村啓和

生体材料工学研究所年報 46 28 - 31 2013.3

Low-Molecular-Weight CXCR4 Ligands with Variable Spacers Reviewed

Tetsuo Narumi, Haruo Aikawa, Tomohiro Tanaka, Chie Hashimoto, Nami Ohashi, Wataru Nomura, Takuya Kobayakawa, Hikaru Takano, Yuki Hirota, Tsutomu Murakami, Naoki Yamamoto, Hirokazu Tamamura

ChemMedChem 8 ( 1 ) 118 - 124 2013.1

Language：English Publishing type：Research paper (scientific journal)

Low-molecular-weight CXCR4 ligands based on known lead compounds including the 14-mer peptide T140, the cyclic pentapeptide FC131, peptide mimetics, and dipicolylamine-containing compounds were designed and synthesized. Three types of aromatic spacers, 1,4-phenylenedimethanamine, naphthalene-2,6-diyldimethanamine, and [1,1′-biphenyl]-4,4′-diyldimethanamine, were used to build four pharmacophore groups. As pharmacophore groups, 2-pyridylmethyl and 1-naphthylmethyl are present in all of the compounds, and several aromatic groups and a cationic group from 1-propylguanidine and 1,1,3,3-tetramethyl-2-propylguanidine were also used. Several compounds showed significant CXCR4 binding affinity, and zinc(II) complexation of bis(pyridin-2-ylmethyl)amine moieties resulted in a remarkable increase in CXCR4 binding affinity. © 2013 WILEY-VCH Verlag GmbH &amp
Co. KGaA, Weinheim.

DOI： 10.1002/cmdc.201200390

Scopus

Bivalent ligands for the chemokine receptor CXCR4 dimer and their function Reviewed

Nomura W, Tanaka T, Aikawa H, Narumi T, Tamamura H

JOURNAL OF PEPTIDE SCIENCE 18 S47 - S47 2012.9

HIV inhibitors targeting entry, fusion, and integrase Reviewed

Narumi Tetsuo, Tanaka Tomohiro, Nomura Wataru, Aikawa Haruo, Tamamura Hirokazu

ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 244 2012.8

Pharmacophore-based small molecule CXCR4 ligands Reviewed

Tetsuo Narumi, Tomohiro Tanaka, Chie Hashimoto, Wataru Nomura, Haruo Aikawa, Akira Sohma, Kyoko Itotani, Miyako Kawamata, Tsutomu Murakami, Naoki Yamamoto, Hirokazu Tamamura

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 22 ( 12 ) 4169 - 4172 2012.6

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

Low molecular weight CXCR4 ligands were developed based on the peptide T140, which has previously been identified as a potent CXCR4 antagonist. Some compounds with naphthyl, fluorobenzyl and pyridyl moieties as pharmacophore groups in the molecule showed significant CXCR4-binding activity and anti-HIV activity. Structure-activity relationships were studied and characteristics of each of these three moieties necessary for CXCR4 binding were defined. In this way, CXCR4 ligands with two types of recognition modes for CXCR4 have been found. (C) 2012 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2012.04.032

Conjugation of cell-penetrating peptides leads to identification of anti-HIV peptides from matrix proteins Reviewed

Tetsuo Narumi, Mao Komoriya, Chie Hashimoto, Honggui Wu, Wataru Nomura, Shintaro Suzuki, Tomohiro Tanaka, Joe Chiba, Naoki Yamamoto, Tsutomu Murakami, Hirokazu Tamamura

BIOORGANIC & MEDICINAL CHEMISTRY 20 ( 4 ) 1468 - 1474 2012.2

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

Compounds which inhibit the HIV-1 replication cycle have been found amongst fragment peptides derived from an HIV-1 matrix (MA) protein. Overlapping peptide libraries covering the whole sequence of MA were designed and constructed with the addition of an octa-arginyl group to increase their cell membrane permeability. Imaging experiments with fluorescent-labeled peptides demonstrated these peptides with an octa-arginyl group can penetrate cell membranes. The fusion of an octa-arginyl group was proven to be an efficient way to find active peptides in cells such as HIV-inhibitory peptides. (C) 2011 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmc.2011.12.055

A Synthetic C34 Trimer of HIV-1 gp41 Shows Significant Increase in Inhibition Potency Reviewed

Wataru Nomura, Chie Hashimoto, Aki Ohya, Kosuke Miyauchi, Emiko Urano, Tomohiro Tanaka, Tetsuo Narumi, Toru Nakahara, Jun A. Komano, Naoki Yamamoto, Hirokazu Tamamura

CHEMMEDCHEM 7 ( 2 ) 205 - 208 2012.2

The successes and failures of HIV drug discovery Reviewed

Chie Hashimoto, Tomohiro Tanaka, Tetsuo Narumi, Wataru Nomura, Hirokazu Tamamura

EXPERT OPINION ON DRUG DISCOVERY 6 ( 10 ) 1067 - 1090 2011.10

Language：English Publisher：INFORMA HEALTHCARE

Introduction: To date, several anti-human immunodeficiency virus (HIV) drugs, including reverse transcriptase inhibitors and protease inhibitors, have been developed and used clinically for the treatment of patients infected with HIV. Recently, novel drugs have been discovered which have different mechanisms of action from those of the above inhibitors, including entry inhibitors and integrase (IN) inhibitors; the clinical use of three of these inhibitors has been approved. Other inhibitors are still in development.
Areas covered: This review article summarizes the history of the development of anti-HIV drugs and also focuses on successes in the development of these entry and IN inhibitors, along with looking at exploratory approaches for the development of other inhibitors.
Expert opinion: Currently used highly active antiretroviral therapy can be subject to a loss of efficacy, due to the emergence of multi-drug resistant (MDR) strains; a change of regimens of the drug combination is required to combat this, along with careful monitoring of the virus and CD4 in the blood, by methods such as cellular tropism testing. In such a situation, entry inhibitors such as CCR5/CXCR4 antagonists, CD4 mimics, fusion inhibitors and IN inhibitors might be optional agents for an expansion of the drug repertoire available to patients at all stages of HIV infection.

DOI： 10.1517/17460441.2011.611129

Azamacrocyclic Metal Complexes as CXCR4 Antagonists Reviewed

Tomohiro Tanaka, Tetsuo Narumi, Taro Ozaki, Akira Sohma, Nami Ohashi, Chie Hashimoto, Kyoko Itotani, Wataru Nomura, Tsutomu Murakami, Yamamoto B. Naoki, Hirokazu Tamamura

CHEMMEDCHEM 6 ( 5 ) 834 - 839 2011.5

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

The chemokine receptor CXCR4 is a member of the seven transmembrane GPCR family, which is implicated in multiple diseases, including HIV infection, cancers, and rheumatoid arthritis. Low-molecular-weight nonpeptidic compounds, including AMD3100 and various pyridyl macrocyclic zinc(II) complexes, have been identified as selective antagonists of CXCR4. In the present study, structure-activity relationship studies were performed by combining the common structural features of alkylamino and pyridiyl macrocyclic antagonists. Several new zinc(II) or copper(II) complexes demonstrated potent anti-HIV activity, strong CXCR4-binding activity, and significant inhibitory activity against Ca(2+) mobilization induced by CXCL12 stimulation. These results may prove useful in the design of novel CXCR4 antagonists, and the compounds described could potentially be developed as therapeutics against CXCR4-relevant diseases or chemical probes to study the biological activity of CXCR4.

DOI： 10.1002/cmdc.201000548

Design and Synthesis of Traceable Linker for Efficient Enrichment and Specific Labeling of Target Proteins Reviewed

Yamamoto Jun, Tanaka Tomohiro, Denda Masaya, Shigenaga Akira, Nomura Wataru, Tamamura Hirokazu, Otaka Akira

BIOPOLYMERS 96 ( 4 ) 492 2011

Development of Bivalent Ligands for CXCR4 with Rigid Linkers and Application to Detection of Cancer Cells Reviewed

Nomura Wataru, Tomohiro Tanaka, Akemi Masuda, Tetsuo Narumi, Hirokazu Tamamura

BIOPOLYMERS 96 ( 4 ) 510 - 511 2011

Synthesis and Application of Fluorescent-labeled Bivalent-type CXCR4 Ligands

Aikawa Haruo, Nomura Wataru, Narumi Tetsuo, Tanaka Tomohiro, Tamamura Hirokazu

Proceedings of the Symposium on Progress in Organic Reactions and Syntheses 37 109 - 109 2011

Language：Japanese Publisher：Division of Organic Chemistry, The Pharmaceutical Society of Japan

We have synthesized bivalent CXCR4 ligands consisting of two molecules of a cyclic pentapeptide cFC131 connected by poly(L-prolines), and the maximum increase in their binding affinity for CXCR4 was observed when the length of linker were 5.5 to 6.5 nm. Here, we synthesized a bivalent ligand with a cyanine dye which would have a property of light absorption and emission in near infrared (NIR) region. Two molecules of cFC131 were conjugated with proline linker through the reaction between the thiol group of cFC131 and the chloroacetyl moiety of proline linker terminals. The obtained azido-peptide was coupled with alkynylcyanine by copper(I)-catalyzed azido/alkyne cycloaddition (CuAAC) reaction. The fluorescent-labeled bivalent ligand was purified by HPLC and characterized by ESI-MS.

DOI： 10.14895/hannou.37.0.109.0

CiNii Article

Bivalent Ligands of CXCR4 with Rigid Linkers for Elucidation of the Dimerization State in Cells Reviewed

Tomohiro Tanaka, Wataru Nomura, Tetsuo Narumi, Akemi Masuda, Hirokazu Tamamura

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 132 ( 45 ) 15899 - 15901 2010.11

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

To date, challenges in the design of bivalent ligands for G protein-coupled receptors (GPCRs) have revealed difficulties stemming from lack of knowledge of the state of oligomerization of the GPCR. The synthetic bivalent ligands with rigid linkers that are presented here can predict the dimer form of CXCR4 and be applied to molecular probes in cancerous cells. This "molecular ruler" approach would be useful in elucidating the details of CXCR4 oligomer formation.

DOI： 10.1021/ja107447w

HIV-1遺伝子産物由来のインテグラーゼ阻害剤の創出 Reviewed

橋本知恵, 田中智博, 浦野恵美子, 尾崎太郎, 新井啓之, 鳴海哲夫, 野村渉, Maddali Kasthuraiah, Pommier Yves, 山本直樹, 駒野淳, 玉村啓和

日本エイズ学会誌 12 ( 4 ) 370 - 370 2010.11

gp120のCD4結合サイトを模倣した新規抗原分子の創製 Reviewed

尾崎太郎, 田中智博, 宮内浩典, 橋本知恵, 鳴海哲夫, 野村渉, 山本直樹, 駒野淳, 玉村啓和

日本エイズ学会誌 12 ( 4 ) 484 - 484 2010.11

HIV-1侵入過程の動的超分子機構を基にした新規エイズワクチンの創製 Reviewed

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

日本エイズ学会誌 12 ( 4 ) 483 - 483 2010.11

CD4 mimics targeting the HIV entry mechanism and their hybrid molecules with a CXCR4 antagonist Reviewed

Tetsuo Narumi, Chihiro Ochiai, Kazuhisa Yoshimura, Shigeyoshi Harada, Tomohiro Tanaka, Wataru Nomura, Hiroshi Arai, Taro Ozaki, Nami Ohashi, Shuzo Matsushita, Hirokazu Tamamura

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 20 ( 19 ) 5853 - 5858 2010.10

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

Small molecules behaving as CD4 mimics were previously reported as HIV-1 entry inhibitors that block the gp120-CD4 interaction and induce a conformational change in gp120, exposing its co-receptor-binding site. A structure-activity relationship (SAR) study of a series of CD4 mimic analogs was conducted to investigate the contribution from the piperidine moiety of CD4 mimic 1 to anti-HIV activity, cytotoxicity, and CD4 mimicry effects on conformational changes of gp120. In addition, several hybrid molecules based on conjugation of a CD4 mimic analog with a selective CXCR4 antagonist were also synthesized and their utility evaluated. (C) 2010 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2010.07.106