Ph.D., Hokkaido University

foldamer

peptidomimetics

ケミカルバイオロジー

医薬分子設計

配座制御

有機合成化学

化合物ライブラリー

脂質代謝

医薬品化学

構造活性相関

Nanotechnology/Materials, Chemical biology

Life Science, Pharmaceutical chemistry and drug development sciences

Bachelor's degree program, School of Pharmaceutical Sciences and Pharmacy

Master's degree program, Graduate School of Life Science

Doctoral (PhD) degree program, Graduate School of Life Science

2020, 北海道大学, 令和元年度（平成31年度）全学教育科目 エクセレント・ティーチャーズ
渡邉 瑞貴, Others

2019, 日本薬学会北海道支部, 奨励賞
渡邉 瑞貴

2018, 有機合成化学協会, ADEKA Award in Synthetic Organic Chemistry, Japan
Mizuki Watanabe

2017, 北海道大学, 平成28年度 全学教育科目 エクセレント・ティーチャーズ
渡邉 瑞貴, Others

2015, 日本ケミカルバイオロジー学会, RSC Molecular BioSystems 賞
渡邉 瑞貴

Amide-to-Chloroalkene Substitution for Peptide Backbone Modification to Enhance Membrane Permeability
Sayuri Takeo; Mio Takeda; Chihiro Iio; Ai Sakakibara; Showmitra Saha; Natsuki Shibata; Yuki Yamazaki; Takahiro Fujii; Ryuhei Harada; Kohei Sato; Nobuyuki Mase; Mizuki Watanabe; Takanori Oyoshi; Tetsuo Narumi
Journal of Medicinal Chemistry, American Chemical Society (ACS), 20 Feb. 2026, [Peer-reviewed], [International Magazine]
English, Scientific journal

Resolvin E1 and Resolvin E2 suppress cyclooxygenase-2 expression through ubiquitin-proteasome-mediated degradation in human macrophage-like U937 cells
Ayaka Hamaguchi; Hayato Fukuda; Mizuki Watanabe; Koichi Fujiwara; Keijo Fukushima; Satoshi Shuto; Hiromichi Fujino
Prostaglandins & Other Lipid Mediators, 183, 107064, 107064, Elsevier BV, Feb. 2026, [Peer-reviewed], [International Magazine]
English, Scientific journal

Design and Synthesis of Cyclopropane Congeners of Resolvin E2 with Azidopropoxy Chain toward a Chemical Tool for Probing the Anti-inflammatory Activity
Hayato Fukuda; Kotaro Matsubara; Ayaka Hamaguchi; Hina Nishikoori; Mayu Shinohara; Jun Takouda; Kohsuke Takeda; Keijo Fukushima; Keita Komine; Koichi Fujiwara; Mizuki Watanabe; Jun Ishihara; Hiromichi Fujino; Satoshi Shuto
The Journal of Organic Chemistry, 91, 1, 466, 476, American Chemical Society (ACS), 19 Dec. 2025, [Peer-reviewed], [International Magazine]
English, Scientific journal

Highly Z-Selective Julia–Kocienski Olefination Using N-Sulfonylimines and Its Mechanistic Insights from DFT Calculations
Takuma Chizaki; Koichi Fujiwara; Junko Fujimoto; Tetsuo Narumi; Satoshi Shuto; Mizuki Watanabe
Organic Letters, 27, 11, 2677, 2681, Mar. 2025, [Peer-reviewed], [Last author, Corresponding author], [International Magazine]
English, Scientific journal, The Julia–Kocienski (JK) olefination is effective for E-selective olefination, but highly Z-selective versions remain rare. Here, we report a highly Z-selective JK olefination (Z ratio >99:1) using N-sulfonylimines as electrophiles instead of aldehydes. This method demonstrates a broad substrate scope, tolerating electron-donating and -withdrawing groups, amides, halogens, carboxylic acids, and hydroxyls. Z-selectivity in our system arises from both the 1,2-addition and Smiles rearrangement steps without involving synperiplanar elimination. This study expands the toolkit for Z-selective olefin synthesis.

Development of aliphatic homo-δ-peptide folders based on rational design
Mizuki Watanabe
月刊 細胞, 55, 9, 69, 72, ニュー・サイエンス社, Jul. 2023, [Invited], [Lead author, Corresponding author], [Domestic magazines]
Japanese

Development of Conformationally Restricted Negamycin Derivatives for Potent Readthrough Activity
Noriko Omura; Akihiro Taguchi; Tomoki Kuwahara; Keisuke Hamada; Mizuki Watanabe; Masanori Nakakuki; Sho Konno; Kentaro Takayama; Atsuhiko Taniguchi; Toshifumi Nomura; Satoshi Shuto; Yoshio Hayashi
ACS Medicinal Chemistry Letters, 14, 12, 1807, 1814, American Chemical Society (ACS), 2023, [Peer-reviewed], [International Magazine]
Scientific journal

Delivering mRNA to Secondary Lymphoid Tissues by Phosphatidylserine‐Loaded Lipid Nanoparticles
Masaki Gomi; Yu Sakurai; Minami Sato; Hiroki Tanaka; Yumi Miyatake; Koichi Fujiwara; Mizuki Watanabe; Satoshi Shuto; Yuta Nakai; Kota Tange; Hiroto Hatakeyama; Hidetaka Akita
Advanced Healthcare Materials, 12, 9, 2202528, Wiley, 2023, [Peer-reviewed], [International Magazine]
English, Scientific journal

Helix-forming aliphatic homo-δ-peptide foldamers based on the conformational restriction effects of cyclopropane
Makoto Nagata; Mizuki Watanabe; Ryohei Doi; Mai Uemura; Nanase Ochiai; Wataru Ichinose; Koichi Fujiwara; Yoshihiro Sato; Tomoshi Kameda; Koh Takeuchi; Satoshi Shuto
Organic & Biomolecular Chemistry, 21, 5, 970, 980, Royal Society of Chemistry (RSC), 2023, [Peer-reviewed], [Corresponding author], [International Magazine]
English, Scientific journal, This work reports the first aliphatic homo-δ-peptide helical foldamer consisting of a conformationally restricted δ-amino acid, where the structural characteristics of cyclopropane tightly control the backbone torsion angles.

Design and Synthesis of Cyclopropane Congeners of Resolvin E3, an Endogenous Pro-Resolving Lipid Mediator, as Its Stable Equivalents
Shota Arai; Koichi Fujiwara; Masahiro Kojima; Haruka Aoki-Saito; Masakiyo Yatomi; Tsugumichi Saito; Yasuhiko Koga; Hayato Fukuda; Mizuki Watanabe; Shigeki Matsunaga; Takeshi Hisada; Satoshi Shuto
The Journal of Organic Chemistry, 87, 15, 10501, 10508, American Chemical Society (ACS), 05 Aug. 2022, [Peer-reviewed], [International Magazine]
English, Scientific journal

Oxytocin Dynamics in the Body and Brain Regulated by the Receptor for Advanced Glycation End-Products, CD38, CD157, and Nicotinamide Riboside
Haruhiro Higashida; Kazumi Furuhara; Olga Lopatina; Maria Gerasimenko; Osamu Hori; Tsuyoshi Hattori; Yasuhiko Hayashi; Stanislav M. Cherepanov; Anna A. Shabalova; Alla B. Salmina; Kana Minami; Teruko Yuhi; Chiharu Tsuji; PinYue Fu; Zhongyu Liu; Shuxin Luo; Anpei Zhang; Shigeru Yokoyama; Satoshi Shuto; Mizuki Watanabe; Koichi Fujiwara; Sei-ichi Munesue; Ai Harashima; Yasuhiko Yamamoto
Frontiers in Neuroscience, 16, 858070, Frontiers Media SA, 07 Jul. 2022, [Peer-reviewed], ［Internationally co-authored］, [International Magazine]
Scientific journal, Investigating the neurocircuit and synaptic sites of action of oxytocin (OT) in the brain is critical to the role of OT in social memory and behavior. To the same degree, it is important to understand how OT is transported to the brain from the peripheral circulation. To date, of these, many studies provide evidence that CD38, CD157, and receptor for advanced glycation end-products (RAGE) act as regulators of OT concentrations in the brain and blood. It has been shown that RAGE facilitates the uptake of OT in mother’s milk from the digestive tract to the cell surface of intestinal epithelial cells to the body fluid and subsequently into circulation in male mice. RAGE has been shown to recruit circulatory OT into the brain from blood at the endothelial cell surface of neurovascular units. Therefore, it can be said that extracellular OT concentrations in the brain (hypothalamus) could be determined by the transport of OT by RAGE from the circulation and release of OT from oxytocinergic neurons by CD38 and CD157 in mice. In addition, it has recently been found that gavage application of a precursor of nicotinamide adenine dinucleotide, nicotinamide riboside, for 12 days can increase brain OT in mice. Here, we review the evaluation of the new concept that RAGE is involved in the regulation of OT dynamics at the interface between the brain, blood, and intestine in the living body, mainly by summarizing our recent results due to the limited number of publications on related topics. And we also review other possible routes of OT recruitment to the brain.

Synthesis of γ-Aminobutyric Acid (GABA) Analogues Conformationally Restricted by Bicyclo[3.1.0]hexane/hexene or [4.1.0]Heptane/heptene Backbones as Potent Betaine/GABA Transporter Inhibitors
Keisuke Mitsui; Maria E. K. Lie; Naoki Saito; Koichi Fujiwara; Mizuki Watanabe; Petrine Wellendorph; Satoshi Shuto
Organic Letters, 24, 23, 4151, 4154, Jun. 2022, [Peer-reviewed], ［Internationally co-authored］, [International Magazine]
English, Scientific journal, Novel γ-aminobutyric acid (GABA) analogues 3-5, having a bicyclo[3.1.0]hexene, [4.1.0]heptane, or [4.1.0]heptene backbone, respectively, were designed from the bioactive form analysis of the previous inhibitor 2 with a bicyclo[3.1.0]hexane backbone. Compounds 3-5 and 2 were synthesized from a common 1,7-diene intermediate 6 using ring-closing metathesis (RCM) to construct the key bicyclo backbones. Compounds 3-5 strongly inhibit betaine/GABA transporter 1 (BGT1) uptake, but compound 4 stands out with its selective low micromolar potency.

Molecular Determinants and Pharmacological Analysis for a Class of Competitive Non-transported Bicyclic Inhibitors of the Betaine/GABA Transporter BGT1
Stefanie Kickinger; Maria EK Lie; Akihiro Suemasa; Anas Al-Khawaja; Koichi Fujiwara; Mizuki Watanabe; Kristine S Wilhelmsen; Christina B Falk-Petersen; Bente Frølund; Satoshi Shuto; Gerhard Franz Ecker; Petrine Wellendorph
Frontiers in Chemistry, 9, 736457, 736457, Sep. 2021, [Peer-reviewed], ［Internationally co-authored］, [International Magazine]
English, Scientific journal, The betaine/GABA transporter 1 (BGT1) is a member of the GABA transporter (GAT) family with still elusive function, largely due to a lack of potent and selective tool compounds. Based on modeling, we here present the design, synthesis and pharmacological evaluation of five novel conformationally restricted cyclic GABA analogs related to the previously reported highly potent and selective BGT1 inhibitor (1S,2S,5R)-5-aminobicyclo[3.1.0]hexane-2-carboxylic acid (bicyclo-GABA). Using [3H]GABA radioligand uptake assays at the four human GATs recombinantly expressed in mammalian cell lines, we identified bicyclo-GABA and its N-methylated analog (2) as the most potent and selective BGT1 inhibitors. Additional pharmacological characterization in a fluorescence-based membrane potential assay showed that bicyclo-GABA and 2 are competitive inhibitors, not substrates, at BGT1, which was validated by a Schild analysis for bicyclo-GABA (pK B value of 6.4). To further elaborate on the selectivity profile both compounds were tested at recombinant α1β2γ2 GABAA receptors. Whereas bicyclo-GABA showed low micromolar agonistic activity, the N-methylated 2 was completely devoid of activity at GABAA receptors. To further reveal the binding mode of bicyclo-GABA and 2 binding hypotheses of the compounds were obtained from in silico-guided mutagenesis studies followed by pharmacological evaluation at selected BGT1 mutants. This identified the non-conserved BGT1 residues Q299 and E52 as the molecular determinants driving BGT1 activity and selectivity. The binding mode of bicyclo-GABA was further validated by the introduction of activity into the corresponding GAT3 mutant L314Q (38 times potency increase cf. wildtype). Altogether, our data reveal the molecular determinants for the activity of bicyclic GABA analogs, that despite their small size act as competitive inhibitors of BGT1. These compounds may serve as valuable tools to selectively and potently target BGT1 in order to decipher its elusive pharmacological role in the brain and periphery such as the liver and kidneys.

Structure, solubility, and permeability relationships in a diverse middle molecule library
Hiroyuki Miyachi; Kayoko Kanamitsu; Mayumi Ishii; Eri Watanabe; Akira Katsuyama; Satoko Otsuguro; Fumika Yakushiji; Mizuki Watanabe; Kouhei Matsui; Yukina Sato; Satoshi Shuto; Takashi Tadokoro; Shunsuke Kita; Takanori Matsumaru; Akira Matsuda; Tomoyasu Hirose; Masato Iwatsuki; Yasuteru Shigeta; Tetsuo Nagano; Hirotatsu Kojima; Satoshi Ichikawa; Toshiaki Sunazuka; Katsumi Maenaka
Bioorganic & Medicinal Chemistry Letters, 37, 127847, 127847, Elsevier BV, Apr. 2021, [Peer-reviewed], [International Magazine]
Scientific journal

Synthesis of Resolvin E1 and Its Conformationally Restricted Cyclopropane Congeners with Potent Anti-Inflammatory Effect
Kohei Ishimura; Hayato Fukuda; Koichi Fujiwara; Ryuta Muromoto; Koki Hirashima; Yuto Murakami; Mizuki Watanabe; Jun Ishihara; Tadashi Matsuda; Satoshi Shuto
ACS Medicinal Chemistry Letters, 12, 2, 256, 261, American Chemical Society (ACS), 11 Feb. 2021, [Peer-reviewed], [International Magazine]
English, Scientific journal

Synthesis of Resolvin E3, a Proresolving Lipid Mediator, and Its Deoxy Derivatives: Identification of 18-Deoxy-resolvin E3 as a Potent Anti-Inflammatory Agent.
Hayato Fukuda; Hiroyuki Ikeda; Ryuta Muromoto; Koki Hirashima; Kohei Ishimura; Koichi Fujiwara; Haruka Aoki-Saito; Takeshi Hisada; Mizuki Watanabe; Jun Ishihara; Tadashi Matsuda; Satoshi Shuto
The Journal of Organic Chemistry, 85, 21, 14190, 14200, 06 Nov. 2020, [Peer-reviewed], [International Magazine]
English, Scientific journal, We synthesized RvE3 and its deoxy derivatives, 17-deoxy-RvE3 and 18-deoxy-RvE3, by a common route via Sonogashira coupling as a key step. The evaluation of their anti-inflammatory activities revealed that 18-deoxy-RvE3 was remarkably more potent than the parent RvE3 and significantly active at a 300 fg dose in mice; additionally, 17-deoxy-RvE3 was significantly less potent than the parent RvE3. For the first time, we found that the 17-hydroxy group of RvE3 is very important for anti-inflammatory activity.

Conformational Restriction of Histamine with a Rigid Bicyclo[3.1.0]hexane Scaffold Provided Selective H3 Receptor Ligands
Mizuki Watanabe; Takaaki Kobayashi; Yoshihiko Ito; Shizuo Yamada; Satoshi Shuto
Molecules (Basel, Switzerland), 25, 16, 05 Aug. 2020, [Peer-reviewed], [Lead author, Corresponding author], [International Magazine]
English, Scientific journal, We designed and synthesized conformationally rigid histamine analogues with a bicyclo[3.1.0]hexane scaffold. All the compounds were selectively bound to the H3 receptor subtype over the H4 receptor subtype. Notably, compound 7 showed potent binding affinity and over 100-fold selectivity for the H3 receptors (Ki = 5.6 nM for H3 and 602 nM for H4). These results suggest that the conformationally rigid bicyclo[3.1.0]hexane structure can be a useful scaffold for developing potent ligands selective for the target biomolecules.

A macrocyclic peptide library with a structurally constrained cyclopropane-containing building block leads to thiol-independent inhibitors of phosphoglycerate mutase.
Rika Okuma; Tomoki Kuwahara; Takafumi Yoshikane; Mizuki Watanabe; Patricia Dranchak; James Inglese; Satoshi Shuto; Yuki Goto; Hiroaki Suga
Chemistry, an Asian journal, 15, 17, 2631, 2636, 07 Jul. 2020, [Peer-reviewed], ［Internationally co-authored］, [International Magazine]
English, Scientific journal, Here we report construction of an mRNA-encoded library of thioether-closed macrocyclic peptides by using an N -chloroacetyl-cyclopropane-containing exotic initiator whose structure is more constrained than the ordinary N -chloroacetyl-α-amino acid initiators. The use of such an initiator has led to a macrocycle library with significantly suppressed population of lariat-shaped species compared with the conventional libraries. We previously used a conventional library and identified a small lariat thioether-macrocycle with a tail peptide with a C-terminal free Cys whose sidechain plays an essential role in potent inhibitory activity against a parasitic model enzyme, phosphoglycerate mutase. On the other hand, the cyclopropane-containing macrocycle library has yielded a larger thioether-macrocycle lacking a free Cys residue, which exhibits potent inhibitory activity to the same enzyme with a different mode of action. This result indicates that such a cyclopropane-containing macrocycle library would allow us to access mechanistically distinct macrocycles.

Design and Synthesis of Benzene Congeners of Resolvin E2, a Proresolving Lipid Mediator, as Its Stable Equivalents
Yuto Murakami; Hayato Fukuda; Ryuta Muromoto; Koki Hirashima; Kohei Ishimura; Koichi Fujiwara; Jun Ishihara; Tadashi Matsuda; Mizuki Watanabe; Satoshi Shuto
ACS Medicinal Chemistry Letters, 11, 4, 479, 484, Apr. 2020, [Peer-reviewed], [International Magazine]
English, Scientific journal

Erratum: Nutrient-based chemical library as a source of energy metabolism modulators (ACS Chemical Biology (2019) 14:9 (1860-1865) DOI: 10.1021/acschembio.9b00444)
Furuta, T.; Mizukami, Y.; Asano, L.; Kotake, K.; Ziegler, S.; Yoshida, H.; Watanabe, M.; Sato, S.-I.; Waldmann, H.; Nishikawa, M.; Uesugi, M.
ACS Chemical Biology, 15, 8, 2311, 2311, 2020
Scientific journal

Erratum: Nutrient-based chemical library as a source of energy metabolism modulators (ACS Chemical Biology (2019) 14:9 (1860-1865) DOI: 10.1021/acschembio.9b00444)
Furuta, T.; Mizukami, Y.; Asano, L.; Kotake, K.; Ziegler, S.; Yoshida, H.; Watanabe, M.; Sato, S.-I.; Waldmann, H.; Nishikawa, M.; Uesugi, M.
ACS Chemical Biology, 15, 8, 2311, 2311, 2020
Scientific journal

Nutrient-Based Chemical Library as a Source of Energy Metabolism Modulators.
Furuta T; Mizukami Y; Asano L; Kotake K; Ziegler S; Yoshida H; Watanabe M; Sato SI; Waldmann H; Nishikawa M; Uesugi M
ACS Chemical Biology, 14, 9, 1860, 1865, Aug. 2019, [Peer-reviewed], ［Internationally co-authored］, [International Magazine]
English, Scientific journal, Covalent conjugates of multiple nutrients often exhibit greater biological activities than each individual nutrient and more predictable safety profiles than completely unnatural chemical entities. Here, we report the construction and application of a focused chemical library of 308 covalent conjugates of a variety of small-molecule nutrients. Screening of the library with a reporter gene of sterol regulatory element-binding protein (SREBP), a master regulator of mammalian lipogenesis, led to the discovery of a conjugate of docosahexaenoic acid (DHA), glucosamine, and amino acids as an inhibitor of SREBP (molecule 1, DHG). Mechanistic analyses indicate that molecule 1 impairs the SREBP activity by inhibiting glucose transporters and thereby activating AMP-activated protein kinase (AMPK). Oral administration of molecule 1 suppressed the intestinal absorption of glucose in mice. These results suggest that such synthetic libraries of nutrient conjugates serve as a source of novel chemical tools and pharmaceutical seeds that modulate energy metabolism.

Synthesis of oxytocin derivatives lipidated via a carbonate or carbamate linkage as a long-acting therapeutic agent for social impairment-like behaviors.
Stanislav M Cherepanov; Risako Miura; Anna A Shabalova; Wataru Ichinose; Shigeru Yokoyama; Hayato Fukuda; Mizuki Watanabe; Haruhiro Higashida; Satoshi Shuto
Bioorganic & Medicinal Chemistry, 27, 15, 3358, 3363, 01 Aug. 2019, [Peer-reviewed], ［Internationally co-authored］, [International Magazine]
English, Scientific journal, In the course of our studies of hydrophobic oxytocin (OT) analogues, we newly synthesized lipidated OT (LOT-4a-c and LOT-5a-c), in which a long alkyl chain (C14-C16) is conjugated via a carbonate or carbamate linkage at the Tyr-2 phenolic hydroxy group and a palmitoyl group at the terminal amino group of Cys-1. These LOTs did not activate OT and vasopressin receptors. Among the LOTs, however, LOT-4c, having a C16-chain via a carbonate linkage at the phenolic hydroxyl group of the Tyr-2, showed very long-lasting action for the recovery of impaired social behavior in CD38 knockout mice, a rodent model of autistic phenotypes, whereas the effect of OT itself rapidly diminished. These results indicate that LOT-4c may serve as a potential prodrug in mice.

Development of a Highly Potent Analogue and a Long-Acting Analogue of Oxytocin for the Treatment of Social Impairment-Like Behaviors.
Wataru Ichinose; Stanislav M Cherepanov; Anna A Shabalova; Shigeru Yokoyama; Teruko Yuhi; Hiroaki Yamaguchi; Ayu Watanabe; Yasuhiko Yamamoto; Hiroshi Okamoto; Shinichi Horike; Junpei Terakawa; Takiko Daikoku; Mizuki Watanabe; Nariyasu Mano; Haruhiro Higashida; Satoshi Shuto
Journal of Medicinal Chemistry, 62, 7, 3297, 3310, 11 Apr. 2019, [Peer-reviewed], ［Internationally co-authored］, [International Magazine]
English, Scientific journal, The nonapeptide hormone oxytocin (OT) has pivotal brain roles in social recognition and interaction and is thus a promising therapeutic drug for social deficits. Because of its peptide structure, however, OT is rapidly eliminated from the bloodstream, which decreases its potential therapeutic effects in the brain. We found that newly synthesized OT analogues in which the Pro7 of OT was replaced with N-( p-fluorobenzyl)glycine (2) or N-(3-hydroxypropyl)glycine (5) exhibited highly potent binding affinities for OT receptors and Ca2+ mobilization effects by selectively activating OT receptors over vasopressin receptors in HEK cells, where 2 was identified as a superagonist ( EMax = 131%) for OT receptors. Furthermore, the two OT analogues had a remarkably long-acting effect, up to 16-24 h, on recovery from impaired social behaviors in two strains of CD38 knockout mice that exhibit autism spectrum disorder-like social behavioral deficits, whereas the effect of OT itself rapidly diminished.

レゾルビンE1はfMLFが誘導するヒト好中球の活性酸素産生を増強する
海野 雄加; 佐藤 義則; 永川 茂; 鴨志田 剛; 西田 智; 上田 たかね; 祖母井 庸之; 斧 康雄; 周東 智; 福田 隼; 石村 航平; 渡邉 瑞貴; 池田 紘之
感染症学雑誌, 93, 臨増, 400, 400, (一社)日本感染症学会, Mar. 2019, [Peer-reviewed], [Domestic magazines]
Japanese

レゾルビンによる好中球活性化のプライミング反応
海野 雄加; 佐藤 義則; 永川 茂; 鴨志田 剛; 西田 智; 上田 たかね; 祖母井 庸之; 斧 康雄; 周 東智; 福田 隼; 石村 航平; 渡邉 瑞貴; 池田 紘之
感染症学雑誌, 93, 1, 71, 71, (一社)日本感染症学会, Jan. 2019, [Peer-reviewed], [Domestic magazines]
Japanese

Synthesis of Enantiomerically Pure 1,2,3-Trisubstituted Cyclopropane Nucleosides Using Pd-Catalyzed Substitution via Directing Group-Mediated C(sp ³ )-H Activation as a Key Step
Minami, T.; Fukuda, K.; Hoshiya, N.; Fukuda, H.; Watanabe, M.; Shuto, S.
Organic Letters, 21, 3, 656, 659, Jan. 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal

Design and synthesis of histamine H₃/H₄ receptor ligands with a cyclopropane scaffold
Mizuki Watanabe; Takaaki Kobayashi; Yoshihiko Ito; Hayato Fukuda; Shizuo Yamada; Mitsuhiro Arisawa; Satoshi Shuto
Bioorganic & Medicinal Chemistry Letters, 28, 23-24, 3630, 3633, 15 Dec. 2018, [Peer-reviewed], [Lead author, Corresponding author], [International Magazine]
English, Scientific journal

Design and synthesis of cyclopropane-based conformationally restricted GABA analogues as selective inhibitors for betaine/GABA transporter 1
Suemasa, A.; Watanabe, M.; Kobayashi, T.; Suzuki, H.; Fukuda, H.; Minami, M.; Shuto, S.
Bioorganic and Medicinal Chemistry Letters, 28, 20, 3395, 3399, Oct. 2018, [Peer-reviewed], [Corresponding author], [International Magazine]
English, Scientific journal

Synthesis of Chiral cis-Cyclopropane Bearing Indole and Chromone as Potential TNFα Inhibitors
Ryutaro Kanada; Makoto Tanabe; Ryuta Muromoto; Yukina Sato; Tomoki Kuwahara; Hayato Fukuda; Mitsuhiro Arisawa; Tadashi Matsuda; Mizuki Watanabe; Satoshi Shuto
Journal of Organic Chemistry, 83, 15, 7672, 7682, 03 Aug. 2018, [Peer-reviewed], [Corresponding author], [International Magazine]
Scientific journal

Resolvin E1, but not resolvins E2 and E3, promotes fMLF-induced ROS generation in human neutrophils.
Yuka Unno; Yoshinori Sato; Hayato Fukuda; Kohei Ishimura; Hiroyuki Ikeda; Mizuki Watanabe; Shigeru Tansho-Nagakawa; Tsuneyuki Ubagai; Satoshi Shuto; Yasuo Ono
FEBS letters, 592, 16, 2706, 2715, Aug. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal, E-series resolvins are biosynthesized from eicosapentaenoic acid during the resolution phase of acute inflammation and enhance inflammation resolution. However, the role of E-series resolvins in inflammation resolution is not yet known. Herein, we show that in human polymorphonuclear neutrophils (PMNs), resolvin E1 (RvE1) selectively enhances reactive oxygen species (ROS) generation induced by N-formylmethionyl-leucyl-phenylalanine. The RvE1-mediated enhancement is eliminated by a pan-antagonist of leukotriene B4 (LTB4) receptors, LY255283, or an NADPH oxidase inhibitor, diphenyleneiodonium. Thus, RvE1 enhances NADPH oxidase-mediated ROS generation via LTB4 receptors. Unlike RvE1, resolvins E2 and E3 do not show such activation of PMNs. Our findings suggest that RvE1 contributes to regulation of ROS generation, in accordance with the inflammatory state of the host.

Live-cell imaging of multiple endogenous mRNAs permits the direct observation of RNA granule dynamics
Kenji Yatsuzuka; Shin-ichi Sato; Kathleen Beverly Pe; Yousuke Katsuda; Ippei Takashima; Mizuki Watanabe; Motonari Uesugi
Chemical Communications, 54, 52, 7151, 7154, Royal Society of Chemistry (RSC), 2018, [Peer-reviewed], [International Magazine]
Scientific journal,

A multicolor RNA imaging technology permits the direct observation of stress granule formation in living cells.

Spiro-cyclopropane type alpha-helix/beta-strand mimetics targeting protein-protein interactions
Kuwahara Tomoki; Mizuno Akira; Fukuda Hayato; Watanabe Mizuki; Shuto Satoshi
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 254, 20 Aug. 2017, [Peer-reviewed]

Synthesis of 8-Substituted Analogues of Cyclic ADP-4-Thioribose and Their Unexpected Identification as Ca²⁺-Mobilizing Full Agonists
Satoshi Takano; Takayoshi Tsuzuki; Takashi Murayama; Tomoshi Kameda; Yasuhiro Kumaki; Takashi Sakurai; Hayato Fukuda; Mizuki Watanabe; Mitsuhiro Arisawa; Satoshi Shuto
Journal of Medicinal Chemistry, 60, 13, 5868, 5875, 13 Jul. 2017, [Peer-reviewed], [International Magazine]
Scientific journal

Vitamin D Metabolite, 25-Hydroxyvitamin D, Regulates Lipid Metabolism by Inducing Degradation of SREBP/SCAP
Lisa Asano; Mizuki Watanabe; Yuta Ryoden; Kousuke Usuda; Takuya Yamaguchi; Bilon Khambu; Megumi Takashima; Shin-ichi Sato; Juro Sakai; Kazuo Nagasawa; Motonari Uesugi
CELL CHEMICAL BIOLOGY, 24, 2, 207, 217, Feb. 2017, [Peer-reviewed]
English, Scientific journal

Cyclopropane-Based Peptidomimetics Mimicking Wide-Ranging Secondary Structures of Peptides: Conformational Analysis and Their Use in Rational Ligand Optimization
Akira Mizuno; Tomoshi Kameda; Tomoki Kuwahara; Hideyuki Endoh; Yoshihiko Ito; Shizuo Yamada; Kimiko Hasegawa; Akihito Yamano; Mizuki Watanabe; Mitsuhiro Arisawa; Satoshi Shuto
Chemistry - A European Journal, 23, 13, 3159, 3168, 2017, [Peer-reviewed]
Scientific journal

Design, Synthesis, and Identification of 4″α-Azidoethyl-cyclic ADP-Carbocyclic-ribose as a Highly Potent Analogue of Cyclic ADP-Ribose, a Ca ²⁺ -Mobilizing Second Messenger
Takatoshi Sato; Mizuki Watanabe; Takayoshi Tsuzuki; Satoshi Takano; Takashi Murayama; Takashi Sakurai; Tomoshi Kameda; Hayato Fukuda; Mitsuhiro Arisawa; Satoshi Shuto
Journal of Medicinal Chemistry, 59, 15, 7282, 7286, 11 Aug. 2016, [Peer-reviewed]
Scientific journal

Live-cell imaging of endogenous mRNAs with a small molecule
Shin-Ichi Sato; Mizuki Watanabe; Yousuke Katsuda; Asako Murata; Dan Ohtan Wang; Motonari Uesugi
Angewandte Chemie - International Edition, 54, 6, 1855, 1858, Wiley-VCH Verlag, 09 Feb. 2015, [Peer-reviewed], [International Magazine]
English, Scientific journal

Synthesis of mevalonate- and fluorinated mevalonate prodrugs and their in vitro human plasma stability
Soosung Kang; Mizuki Watanabe; J. C. Jacobs; Masaya Yamaguchi; Samira Dahesh; Victor Nizet; Thomas S. Leyh; Richard B. Silverman
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 90, 448, 461, Jan. 2015, [Peer-reviewed], [International Magazine]
English, Scientific journal

Synthetic Molecules that Protect Cells from Anoikis and Their Use in Cell Transplantation
Heidie L. Frisco-Cabanos; Mizuki Watanabe; Naoki Okumura; Kosuke Kusamori; Naohiro Takemoto; Junichiro Takaya; Shin-ichi Sato; Sayumi Yamazoe; Yoshinobu Takakura; Shigeru Kinoshita; Makiya Nishikawa; Noriko Koizumi; Motonari Uesugi
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 53, 42, 11208, 11213, Oct. 2014, [Peer-reviewed]
English, Scientific journal

Preparation of chiral bromomethylenecyclopropane and its use in Suzuki-Miyaura coupling: Synthesis of the arylmethyl-(Z)-cyclopropane structure core
Makoto Tanabe; Mizuki Watanabe; Naoyuki Hoshiya; Akira Mizuno; Hayato Fukuda; Mitsuhiro Arisawa; Satoshi Shuto
Journal of Organic Chemistry, 78, 23, 11714, 11720, 06 Dec. 2013, [Peer-reviewed]
Scientific journal

Small-molecule inhibitors of SREBP activation - potential for new treatment of metabolic disorders
Mizuki Watanabe; Motonari Uesugi
MEDCHEMCOMM, 4, 11, 1422, 1433, Nov. 2013, [Peer-reviewed]
English

Three-dimensional structural diversity-oriented peptidomimetics based on the cyclopropylic strain
Akira Mizuno; Shiho Miura; Mizuki Watanabe; Yoshihiko Ito; Shizuo Yamada; Takenao Odagami; Yuji Kogami; Mitsuhiro Arisawa; Satoshi Shuto
Organic Letters, 15, 7, 1686, 1689, Apr. 2013, [Peer-reviewed]
Scientific journal

Cyclopropane-based stereochemical diversity-oriented conformational restriction strategy: Histamine H 3 and/or H 4 receptor ligands with the 2,3-methanobutane backbone
Mizuki Watanabe; Takaaki Kobayashi; Takatsugu Hirokawa; Akira Yoshida; Yoshihiko Ito; Shizuo Yamada; Naoki Orimoto; Yasundo Yamasaki; Mitsuhiro Arisawa; Satoshi Shuto
Organic and Biomolecular Chemistry, 10, 4, 736, 745, 28 Jan. 2012, [Peer-reviewed]
Scientific journal

Synthesis of a series of 3,4-methanoarginines as side-chain conformationally restricted analogues of arginine
Mizuki Watanabe; Kazuya Yamaguchi; Wei Tang; Keisuke Yoshida; Richard B. Silverman; Mitsuhiro Arisawa; Satoshi Shuto
Bioorganic and Medicinal Chemistry, 19, 20, 5984, 5988, 15 Oct. 2011, [Peer-reviewed], [Lead author], ［Internationally co-authored］, [International Magazine]
Scientific journal

Investigation of the bioactive conformation of histamine H3 receptor antagonists by the cyclopropylic strain-based conformational restriction strategy
Mizuki Watanabe; Takatsugu Hirokawa; Takaaki Kobayashi; Akira Yoshida; Yoshihiko Ito; Shizuo Yamada; Naoki Orimoto; Yasundo Yamasaki; Mitsuhiro Arisawa; Satoshi Shuto
Journal of Medicinal Chemistry, 53, 9, 3585, 3593, 13 May 2010, [Peer-reviewed]
Scientific journal

Synthesis and structural and pharmacological properties of cyclopropane-based conformationally restricted analogs of 4-methylhistamine as histamine H3/H4 receptor ligands
Takaaki Kobayashi; Mizuki Watanabe; Akira Yoshida; Shizuo Yamada; Mika Ito; Hiroshi Abe; Yoshihiro Ito; Mituhiro Arisawa; Satoshi Shuto
Bioorganic and Medicinal Chemistry, 18, 3, 1076, 1082, 01 Feb. 2010, [Peer-reviewed]
Scientific journal

Stereochemical diversity-oriented conformational restriction strategy. Development of potent histamine H-3 and/or H-4 receptor antagonists with an imidazolylcyclopropane structure
Mizuki Watanabe; Yuji Kazuta; Hideki Hayashi; Shizuo Yamada; Akira Matsuda; Satoshi Shuto
JOURNAL OF MEDICINAL CHEMISTRY, 49, 18, 5587, 5596, Sep. 2006, [Peer-reviewed]
English, Scientific journal

P-253 DEVELOPMENT OF POTENT HISTAMINE H_3 AND/OR H_4 RECEPTOR ANTAGONISTS BY THE STEREOCHEMICAL DIVERSITY-ORIENTED CONFORMATIONAL RESTRICTION STRATEGY
Watanabe Mizuki; Kazuta Yuji; Hayashi Hideki; Yamada Shizuo; Matsuda Akira; Shuto Satoshi
International Symposium on the Chemistry of Natural Products, 2006, "P, 253", Symposium on the chemistry of natural products, 23 Jul. 2006
English

Development of Spirocyclopropane-Based Peptidomimetics Targeting α-Helix Hot Spots
山崎祐季; 坂下遼太郎; 桑原智希; 長友優典; 竹内恒; 周東智; 渡邉瑞貴, 日本薬学会年会要旨集(Web), 145th, 2025

Evaluation of whether middle molecules are substrates for P-gp using P-gp-overexpressing cells
柏木仁; 山田隼大; 王子谷健太; 佐藤夕紀; 梨本俊亮; 渡邉瑞貴; 廣瀬友靖; 廣瀬友靖; 岩月正人; 岩月正人; 砂塚敏明; 砂塚敏明; 金光佳世子; 石井真由美; 渡邊恵里; 宮地弘幸; 武隈洋; 菅原満; 菅原満, 日本薬学会年会要旨集(Web), 145th, 2025

レゾルビンEシリーズとその誘導体の抗炎症作用の検討
浜口綾花; 福田隼; 松原光太郎; 藤原広一; 渡邉瑞貴; 福島圭穣; 周東智; 藤野裕道, 生体機能と創薬シンポジウム要旨集, 2024, 2024

Development research of STAT3 inhibitors with a cyclopropane scaffold
渡邉瑞貴; 林真由; 太田克美; 浅井章良; 周東智, 日本薬学会年会要旨集(Web), 143rd, 2023

Structure and solubility, passive diffusivity, cell membrane permeability, and P-gp substrate properties of optically active cyclopropane-containing cyclic peptides.
宮地弘幸; 金光佳世子; 石井真由美; 渡邊恵里; 佐藤優希菜; 長田貴行; 山崎祐季; 柏木仁; 菅原満; 周東智; 重田育照; 渡邉瑞貴; 前仲勝実, 日本薬学会年会要旨集(Web), 143rd, 2023

GABAトランスポーターBGT1選択的阻害剤の設計と合成
周東智; 三井桂佑; 斎藤直希; 藤原広一; 渡邊瑞貴; LIE Maria E. K.; WELLENDORPH Petrine, 反応と合成の進歩シンポジウム講演要旨集, 48th, 2022

Michael-Wittig反応によるスキップジエン構築を鍵反応とするレゾルビンE4およびdeoxy体の合成研究
櫻田海都; 藤原広一; 渡邉瑞貴; 周東智, 反応と合成の進歩シンポジウム講演要旨集, 48th, 2022

Synthesis of conformationally restricted negamycin derivatives and its readthrough activity
大村紀子; 田口晃弘; 浜田圭佑; 桑原智希; 渡邉瑞貴; 中久木正則; 今野翔; 高山健太郎; 谷口敦彦; 乃村俊史; 乃村俊史; 周東智; 林良雄, 日本薬学会年会要旨集(Web), 142nd, 2022

Development of membrane-permeable cyclic peptides based on conformational restriction using cyclopropane
高島悠太; 山崎祐季; 佐藤優希菜; 植村麻衣; 松井耕平; 藤原広一; 渡邉瑞貴; 周東智, 日本薬学会年会要旨集(Web), 142nd, 2022

Development of novel peptide foldamers based on cyclopropane amino acids
渡邉瑞貴, 日本薬学会年会要旨集(Web), 142nd, 2022

1,2,3-三置換シクロプロパンを骨格とするSTAT3阻害剤の創製研究
林真由; 甘利穂乃花; 太田克美; 藤原広一; 渡邉瑞貴; 浅井章良; 周東智, 反応と合成の進歩シンポジウム講演要旨集, 48th, 2022

抗炎症脂質レゾルビンE2の1,4,7-トリエン-ベンゼン置換による安定等価体の創製研究
田中伸英; 村上侑斗; 平島洸基; 福田隼; 藤原広一; 渡邉瑞貴; 室本竜太; 松田正; 周東智, 反応と合成の進歩シンポジウム講演要旨集, 48th, 2022

Synthetic study of stable bioisostere of antiinflammatory lipid mediator RvE3
新井将太; 藤原広一; 福田隼; 渡邉瑞貴; 青木遥; 矢冨正清; 古賀康彦; 齋藤従道; 久田剛志; 周東智, 日本薬学会年会要旨集(Web), 141st, 2021

強力な抗炎症活性を有するレゾルビンE1の安定誘導体の創出研究
小坂篤生; 藤原広一; 渡邉瑞貴; 周東智, 反応と合成の進歩シンポジウム講演要旨集, 47th, 2021

逆マルコフニコフ型アルキンヒドロアミノ化による3-デアザアデニン環の構築と応用
今田圭祐; 山田真輝; 藤原広一; 渡邉瑞貴; 周東智, 反応と合成の進歩シンポジウム講演要旨集, 47th, 2021

Study of Bcl-2 Family Protein Inhibitors Based on the Spirocyclopropane Peptidomimetics
坂下遼太郎; 桑原智希; 藤原広一; 渡邉瑞貴; 周東智, 複素環化学討論会講演要旨集, 50th, 2021

Synthetic Study of Ansamycin Natural Product Cytotrienin A
坂田淳; 佐藤晋平; 小嶺敬太; 福田隼; 渡邉瑞貴; 周東智; 石原淳, 複素環化学討論会講演要旨集, 50th, 2021

Synthetic study of 6”-fluoro-8-substituted analogues of cyclic ADP-ribose (cADPR), a Ca²⁺ mobilizing second messenger, as a stable antagonists of cADPR
佐竹俊哉; 横井健斗; 藤原広一; 渡邉瑞貴; 周東智, 複素環化学討論会講演要旨集, 49th, 2020

炎症収束性脂質レゾルビン類をプロトタイプとする創薬化学研究
藤原広一; 村上侑斗; 池田紘之; 福田隼; 石原淳; 渡邉瑞貴; 周東智, 反応と合成の進歩シンポジウム講演要旨集, 2020

Evaluation of membrane permeability and absorbability of cyclic peptides introduced tethers of cyclopropane
加藤七海; 植村真衣; 松井耕平; 渡邉瑞貴; 武隈洋; 周東智; 菅原満; 菅原満, 日本薬学会年会要旨集(Web), 140th, 2020

Construction and application of cyclopropane-containing macrocyclic peptide libraries
大熊里佳; 桑原智希; 渡邉瑞貴; 周東智; 後藤佑樹; 菅裕明, 日本化学会春季年会講演予稿集(CD-ROM), 100th, 2020

Synthetic study of stable bioisostere of antiinflammatory lipid mediator RvE3
新井将太; 藤原広一; 渡邉瑞貴; 周東智, 万有札幌シンポジウム, 32nd, 2020

Design and synthesis of novel helical foldamers based on the cyclopropane δ-amino acid
Mizuki Watanabe, 日本薬学会年会要旨集(Web), 140th, 2020

炎症収束脂質レゾルビンE2のスキップジエン構造をベンゼン環で置換した安定等価体創製研究
村上 侑斗; 福田 隼; 石村 航平; 平島 洸基; 室本 竜太; 渡邉 瑞貴; 松田 正; 周東 智, 日本薬学会年会要旨集, 139年会, 2, 96, 96, Mar. 2019
(公社)日本薬学会, Japanese

EPA由来抗炎症性代謝産物(レゾルビン)の糖代謝における検討
清水智彦; 斎藤従道; 藤原広一; 渡邉瑞貴; 植原良太; 岡田純一; 澁澤良; 下田容子; 笠井裕子; 大崎綾; 山田英二郎; 岡田秀一; 周東智; 山田正信, 日本内分泌学会雑誌, 95, 1, 2019

配座制御を鍵とした分子設計によるGABAトランスポーターBGT-1サブタイプ選択的阻害薬の創製研究
三井桂佑; 末政亮大; 小林嵩明; 人羅菜津子; 藤原広一; 渡邉瑞貴; 南雅文; WELLENDORPH Petrine; 周東智, メディシナルケミストリーシンポジウム講演要旨集, 37th, 2019

EPA由来新規抗炎症性代謝産物(レゾルビンE群)の糖代謝における検討
清水智彦; 齋藤従道; 渡邉瑞貴; 藤原広一; 植原良太; 岡田純一; 澁澤良; 下田容子; 笠井裕子; 大崎綾; 山田英二郎; 岡田秀一; 周東智; 山田正信, 糖尿病(Web), 62, Suppl, 2019

配座制御を基盤とした機能性オリゴペプチドの創出
渡邉瑞貴, 上原記念生命科学財団研究報告集(CD-ROM), 33, 2019

環状ペプチド低分子化方法論の確立を目指した三次元多様型シクロプロパンペプチドミメティクスの開発研究
杉山洸; 一ノ瀬亘; 渡邉瑞貴; 広川貴次; 周東智, 日本薬学会年会要旨集(CD-ROM), 139th, 2019

スピロシクロプロパン型αヘリックス・βストランドミメティクスに基づくp53/MDM2結合阻害剤の創製
桑原智希; 水野彰; 渡邉瑞貴; 竹内恒; 広川貴次; 浅井章良; 周東智, 日本薬学会年会要旨集(CD-ROM), 139th, 2019

サイトトリエニンAの合成研究
佐藤晋平; 福田隼; 渡邉瑞貴; 周東智, 反応と合成の進歩シンポジウム講演要旨集, 44th, 12, 15 Oct. 2018
Japanese

Pd触媒を用いたC(sp³)‐H活性化反応を鍵段階とする光学活性1,2,3‐三置換シクロプロパンヌクレオシドの合成
南貴覚; 福多洸太朗; 星谷尚亨; 福田隼; 渡邉瑞貴; 周東智, 反応と合成の進歩シンポジウム講演要旨集, 44th, 107, 15 Oct. 2018
Japanese

シクロプロパンの構造特性に基づく膜透過性環状ペプチドの設計と合成
植村真衣; 加藤七海; 松井耕平; 桑原智希; 渡邉瑞貴; 福田隼; 武隈洋; 菅原満; 周東智, 日本薬学会年会要旨集(CD-ROM), 138年会, 2, 116, 116, Mar. 2018
(公社)日本薬学会, Japanese

GABAトランスポーターサブタイプ選択的阻害剤の創出を目的とするGABA配座制限誘導体の設計と合成
末政亮大; 中田和彰; 小林嵩明; 福田隼; 渡邉瑞貴; 井手聡一郎; 人羅菜津子; 南雅文; 周東智, 日本薬学会年会要旨集(CD-ROM), 138年会, 2, 113, 113, Mar. 2018
(公社)日本薬学会, Japanese

trans‐1,2‐シクロプロパンジアミンおよびジカルボン酸からなるオリゴアミドの合成研究
山田圭恭; 一ノ瀬亘; 福田隼; 渡邉瑞貴; 周東智, 日本薬学会年会要旨集(CD-ROM), 138th, ROMBUNNO.26L‐am03S, 2018
Japanese

シクロプロパンの立体及び立体電子特性に基づくペプチドミメティクス―αヘリックス/βストランドミメティクス及び膜透過ミメティクスの開発―
桑原智希; 植村真衣; 水野彰; 一ノ瀬亘; 松井耕平; 福田隼; 渡邉瑞貴; 周東智, 反応と合成の進歩シンポジウム講演要旨集, 43rd, 149, 16 Oct. 2017
Japanese

1‐アルキル‐3‐デアザアデニン環の構築を鍵とした3‐デアザ‐cADPcRの合成
山田真輝; 金田龍太郎; 高木耕治; 福田隼人; 渡邉瑞貴; 周東智, 複素環化学討論会講演要旨集, 47th, 82, 10 Oct. 2017
Japanese

光学活性1,2,3‐三置換シクロプロパンヌクレオシドの合成
南貴覚; 福多洸太朗; 星谷直亨; 福田隼; 渡邉瑞貴; 周東智, 万有札幌シンポジウム, 29th, 47, 01 Jul. 2017
Japanese

炎症収束性脂質レゾルビンE1配座制限誘導体の設計と合成
石村航平; 福田隼; 室本竜太; 平島洸基; 渡邉瑞貴; 松田正; 周東智, 次世代を担う有機化学シンポジウム講演要旨集, 15th, 26‐27, 19 May 2017
Japanese

シクロプロパンの構造特性に基づく環状ペプチド膜透過性の飛躍的向上
植村真衣; 松井耕平; 桑原智希; 渡邉瑞貴; 福田隼; 加藤七海; 武隈洋; 菅原満; 周東智, 日本薬学会年会要旨集(CD-ROM), 137年会, 2, 120, 120, Mar. 2017
(公社)日本薬学会, Japanese

25‐ヒドロキシビタミンDによるSREBP‐SCAPの分解メカニズムの解明
浅野理沙; 渡邉瑞貴; 領田優太; 長澤和夫; 上杉志成, 日本薬学会年会要旨集(CD-ROM), 137th, ROMBUNNO.25R‐pm14S, 2017
Japanese

シクロプロパン構造特性に基づくレゾルビンE2の安定等価体の創製研究
松原光太郎; 池田紘之; 石村航平; 平島洸基; 室本竜太; 松田正; 福田隼; 渡邉瑞貴; 周東智, 日本薬学会年会要旨集(CD-ROM), 137th, 2, ROMBUNNO.27R‐am10S, 120, 2017
(公社)日本薬学会, Japanese

サイトトリエニンAの合成研究
佐藤晋平; 福田隼; 渡邉瑞貴; 周東智, 日本薬学会年会要旨集(CD-ROM), 137th, ROMBUNNO.27S‐pm09S, 2017
Japanese

内因性炎症収束脂質レゾルビン類の創薬化学研究
池田紘之; 福田隼; 高倉夕季; 石村航平; 平島洸基; 平尾徹; 室本竜太; 渡邉瑞貴; 松田正; 周東智, メディシナルケミストリーシンポジウム講演要旨集, 34th, 143, 11 Nov. 2016
Japanese

IP₃シグナル伝達系解析分子としてのアデノホスチン誘導体の設計と合成
渡邉瑞貴; 大浦泰; 森川優輝; 福田隼; 森田貴雄; 谷村明彦; 周東智, 反応と合成の進歩シンポジウム講演要旨集, 42nd, 11, 21 Oct. 2016
Japanese

スピロシクロプロパン型αヘリックス/βストランドミメティクスの設計と合成
桑原智希; 水野彰; 福田隼; 渡邉瑞貴; 神田敦宏; 石田晋; 周東智, 万有生命科学振興国際交流財団札幌シンポジウム, 28th, 61, 02 Jul. 2016
Japanese

三次元多様性を鍵とする分子設計に基づくGABAトランスポーターBGT‐1サブタイプ高選択的阻害剤の創製
末政亮大; 中田和彰; 小林嵩明; 福田隼; 渡邉瑞貴; 柴野さや子; 井川ありさ; 井手聡一郎; 南雅文; 周東智, 次世代を担う有機化学シンポジウム講演要旨集, 14th, 28‐29, 19 May 2016
Japanese

ケミカルバイオロジーによるビタミンD誘導体の新機能研究
渡邉瑞貴; 浅野理沙; 長澤和夫; 上杉志成, 日本薬学会年会要旨集(CD-ROM), 136th, ROMBUNNO.S16‐3, 2016
Japanese

内因性低分子化合物による新規脂質代謝制御メカニズムの解明
浅野理沙; 渡邉瑞貴; 領田優太; 長澤和夫; 上杉志成, 日本薬学会年会要旨集(CD-ROM), 135th, ROMBUNNO.26R-PM24, 2015
Japanese

脂質生合成を抑制する内因性小分子化合物
渡邉瑞貴; 浅野理沙; 領田優太; KHAMBA Bilon; 薄田晃佑; 飯田圭介; 岩田淳; 佐藤慎一; 長澤和夫; 上杉志成, 天然有機化合物討論会講演要旨集(Web), 56th, 85‐89(J‐STAGE), 2014
Japanese

Design, Synthesis, and Validation of Peptidomimetics with Three-Dimensional Structural Diversity
MIZUNO Akira; MIURA Shiho; WATANABE Mizuki; KAMEDA Tomoshi; ARISAWA Mitsuhiro; SHUTO Satoshi, Peptide science : proceedings of the ... Japanese Peptide Symposium, 2012, 9, 10, 01 Mar. 2013
English

光学活性メチレンシクロプロパンを鍵ユニットとする低分子TNF‐α阻害剤の創製研究
田辺真人; 渡邉瑞貴; 水野彰; 有澤光弘; 周東智, 複素環化学討論会講演要旨集, 42nd, 355, 356, 30 Sep. 2012
Japanese

光学活性ブロモメチレンシクロプロパンを用いる鈴木‐宮浦クロスカップリングとTNF‐α阻害剤合成への応用
田辺真人; 渡邉瑞貴; 水野彰; 有澤光弘; 周東智, 日本薬学会年会要旨集, 132nd, 2, 136, 05 Mar. 2012
Japanese

光学活性ブロモメチレンシクロプロパンを用いる鈴木‐宮浦クロスカップリング
田辺真人; 渡邉瑞貴; 水野彰; 有澤光弘; 周東智, 万有生命科学振興国際交流財団札幌シンポジウム, 23rd, 59, 02 Jul. 2011
Japanese

光学活性ブロモメチレンシクロプロパンを用いる鈴木‐宮浦クロスカップリング反応
田辺真人; 渡邉瑞貴; 水野彰; 有澤光弘; 周東智, 日本薬学会年会要旨集, 131st, 2, 87, 05 Mar. 2011
Japanese

Stereochemical Diversity-Oriented Design of Cyclopropane-Based Peptidomimetics –Development of Melanocortin Receptor Ligands–
Mizuno Akira; Miura Shiho; Watanabe Mizuki; Odagami Takenao; Kogami Yuji; Arisawa Mitsuhiro; Shuto Satoshi, Proceedings of the Symposium on Progress in Organic Reactions and Syntheses, 37, 11, 11, 2011
Development of an efficient methodology to identify and mimic the bioactive conformation of a GPCR-binding peptide ligand is described. We designed the cyclopropane-based peptidomimetics that are composed of eight stereoisomers and can mimic various three-dimensional structures of tetrapeptide. The peptidomimetic strategy was applied to design melanocortin receptor (MCR) ligands based on the active residues of the endogenous MCR ligands, i.e. His-Phe-Arg-Trp. The mimetics were synthesized from chiral epichlorohydrin via the diastereoselective Grignard reaction on sulfinylimine as the key step. From the structure-activity relationship study of the eight stereoisomers, mimetic ent-1 was found to mimic the bioactive conformation of the active tetrapeptide moiety. Using ent-1 as a lead, a more potent MC4R ligand ent-1-C₄Ph was developed., Division of Organic Chemistry, The Pharmaceutical Society of Japan, Japanese

シクロプロパン歪みに基づくヒスタミンH₃受容体リガンドの設計と活性配座解析
小林嵩明; 渡辺瑞貴; 広川貴次; 吉田徳; 伊藤由彦; 山田静雄; 有澤光弘; 周東智, メディシナルケミストリーシンポジウム講演要旨集, 28th, 2009

Stereochemical Diversity-Oriented Conformational Restriction Strategy : Development of Potent Histamine H₃/H₄ Receptor Ligands by the Chiral Cyclopropnae Units.
Watanabe Mizuki; Kzuta Yuji; Arisawa Mitsuhiro; Matsuda Akira; Shuto Satoshi, Proceedings of the Symposium on Progress in Organic Reactions and Syntheses, 32, 132, 132, 2006
We have presented "the stereochemical diversity-oriented conformational restriction strategy", which is effective in developing specific ligands for various drug target proteins. For using this strategy, we developed the versatile chiral cyclopropane units, (1S,2R)- and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane or their enantiomers. These units were employed to design and synthesize a series of conformationally restricted analogues of histamine with a chiral cis- or trans-cyclopropane structure. Thus, we successfully identified a potent histamine H₃ receptor agonist AEIC [(1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane] and also a potent H₄ receptor antagonist CAIC [(1R,2S)-2-[2-(4-chlorobenzylamino)ethyl]-1-(1H-imidazol-4-yl)- cyclopropane]., Division of Organic Chemistry, The Pharmaceutical Society of Japan, Japanese

立体的多様性を鍵とする分子設計―ヒスタミンH₃受容体あるいはH₄受容体選択的アンタゴニストの創製―
渡邉瑞貴; 数田雄二; 林秀樹; 山田静雄; 松田彰; 周東智, メディシナルケミストリーシンポジウム講演要旨集, 24th, 200, 201, 10 Nov. 2005
Japanese

新スタンダード薬学シリーズ第3巻 基礎薬学 IV.有機化学
第15章 アミン
東京化学同人, Jul. 2024, 9784807917365, Textbook, [Contributor]

The Frontier of Peptide Drug Discovery
第12章 環状ペプチドの三次元構造制御による膜透過性の飛躍的向上
シーエムシー出版, May 2019, 9784781314174, Japanese, Scholarly book, [Contributor]

主鎖配座制御によるタンパク質二次構造ミメティクスの創出研究
渡邉瑞貴
生物物理 次世代NMR 金曜spin-off会, 26 Jul. 2024, Nominated symposium
[Invited]

シクロプロパン骨格を有するSTAT3阻害剤の創出研究
渡邉瑞貴
日本薬学会第143年会 一般シンポジウム「JAK-STATサイトカインシグナル伝達系 ーその発見から臨床現場へー」, 28 Mar. 2023
[Invited]

“カタチ”を意識した分子設計に基づく創薬化学研究
渡邉瑞貴
静岡大学総合科学技術研究科 有用物質合成研究会, 20 Jan. 2023, Public discourse
[Invited]

シクロプロパンによる配座制御を基軸としたペプチドフォルダマーの開発
渡邉瑞貴
日本薬学会第142年会 一般シンポジウム「フォルダマーの魅力 ―構造多様性が拓く未来―」, 27 Mar. 2022
[Invited]

シクロプロパンδ-アミノ酸を基盤としたヘリカルフォルダマーの開発
渡邉瑞貴
日本薬学会第140年会 一般シンポジウム「フォルダマーの魅力 ーペプチド創薬のパラダイムシフトー」, 27 Mar. 2020
[Invited]

配座制御による環状ペプチドの膜透過性の向上
渡邉 瑞貴
第14回トランスポーター研究会, 20 Jul. 2019
[Invited]

配座制御を基盤とした分子設計による創薬化学研究
渡邉 瑞貴
日本薬学会北海道支部第146回例会, 18 May 2019, Japanese, Invited oral presentation
[Invited], [Domestic Conference]

ペプチドの"形"を制御して"機能"を変える
渡邉 瑞貴
第50回若手ペプチド夏の勉強会, 07 Aug. 2018, Japanese, Nominated symposium
[Invited]

配座制御を基盤とした機能性ペプチドの開発
渡邉 瑞貴
有機合成化学協会北海道支部「若手研究者のための有機化学札幌セミナー」, 28 Nov. 2017, Japanese
[Invited]

Development of conformationally restricted peptides and peptidomimetics based on the structural features of cyclopropane
Mizuki Watanabe
The 3rd HU-TMU-KU Joint Symposium for Pharmaceutical Sciences, 01 Sep. 2017, English, Invited oral presentation
[Invited], [International presentation]

ケミカルバイオロジーによるビタミンD誘導体の新機能研究
渡邉 瑞貴
日本薬学会第136年会 一般シンポジウム「有機合成化学の若い力：有機分子との格闘と対話」, 27 Mar. 2016, Japanese, Nominated symposium
[Invited]

Development of the small molecules that control the lipid biosynthesis
Mizuki Watanabe
2012 Seminar Series in Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 14 Jun. 2012, English, Nominated symposium
[Invited]

創薬化学特論, 2024年, 修士課程, 生命科学院

化学Ⅱ, 2024年, 学士課程, 全学教育

有機化学実習Ⅰ, 2024年, 学士課程, 薬学部

有機化学実習Ⅱ, 2024年, 学士課程, 薬学部

主鎖配座制御を基盤としたタンパク質二次構造ミメティクスの創薬研究
科学研究費助成事業
Apr. 2025 - Mar. 2028
渡邉 瑞貴
日本学術振興会, 基盤研究(C), 北海道大学, Principal investigator, Competitive research funding, 25K09887

Development Research on Peptide Foldamers Based on Conformationally Restricted Amino Acids
Grants-in-Aid for Scientific Research
Apr. 2022 - Mar. 2025
渡邉 瑞貴
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, Principal investigator, Competitive research funding, 22K06494

三次元構造制御を鍵とした分子設計に基づく機能性ペプチドの開発
科学研究費助成事業
Apr. 2019 - Mar. 2023
渡邉 瑞貴
本研究では、細胞内タンパク質間相互作用を標的可能な新たなペプチド創薬方法論の確立を目指し、分子全体の三次元構造を制御することによって機能化したペプチドの創製に取り組んだ。具体的には、キラルシクロプロパンの構造特性を利用して配座を高度に制御した光学活性シクロプロパンδ-アミノ酸を鍵ユニットとした分子設計による、タンパク質間相互作用に重要なαヘリックス上の側鎖官能基の空間配置を模倣したペプチドフォルダマー、および、配座制御によって高い細胞膜透過性を有した環状ペプチドの設計・合成・立体構造解析を実施した。まず、分子動力学計算を活用し、三次元構造を予測をしながら、シクロプロパンの構造特性を利用して配座を高度に制御した光学活性シクロプロパンδ-アミノ 酸を鍵ユニットとしたオリゴマーや環状ペプチドの分子設計を行った。次に、分子設計した分子の有機化学合成に取り組んだ。トランス形シクロプロパンユニットは、光学活性グリシドールを出発原料とし、立体選択的なシクロプロパン構築反応、不斉補助基を利用した立体選択的Grignard反応、および、不斉アルキル化を経て、18工程で合成した。シス形シクロプロパンユニットは、光学活性エピクロロヒドリンから立体選択的にシクロプロパン骨格を構築し、ヒドロホウ素化からのシス選択的な酸化反応などを経て合成した。昨年度に引き続き、当該年度も新たに、シクロプロパンδ-アミノ酸ユニットを基盤としたオリゴマーを設計・合成した。 合成したオリゴマーの溶液中での三次元構造を、詳細なNMR解析によって確認した。また、合成した各種環状ペプチドの膜透過性を人工膜を用いた透過性評価システム（PAMPA）によって評価した。
日本学術振興会, 基盤研究(C), 北海道大学, Principal investigator, 19K06965

高分子間相互作用を制御する合成機能分子を論理的・効率的に創出する方法論の確立
科学研究費助成事業
Apr. 2019 - Mar. 2023
周東 智; 渡邉 瑞貴; 小松 康雄; 藤原 広一; 後藤 佑樹
創薬においてランダムスクリーニングが汎用されている現在、標的分子に選択的に結合する化合物を偶然に依存することなく論理的に創出する方法論の確立は、アカデミアとしての化学系薬学が取り組むべき最重要課題である。このような現状に鑑み、本研究は、独自に考案したシクロプロパンの構造特性に基づく三次元多様性を鍵概念とする論理的分子設計を、タンパク質間相互作用（PPI）等の高分子間相互作用の制御へと展開することが可能であることを実証し、高分子間相互作用を制御する合成医薬創出の論理的方法論を提示すること目的とする。また、有機合成化学に裏付けられた独自の分子設計戦略が、本研究の独創性に優れる利点である。
本年度の主な実績は以下の通りである。課題1. 汎用性αヘリックスミメティクスの創出研究においては、精密な配座制御を施した独自のスピロシクロプロパン骨格scaffold II に基づき、制癌標的であるBcl-2ファミリータンパク質を標的とするミメティクスを設計・合成した。課題2. 細胞膜透過性PPI制御環状ペプチドの創出研究においては、制癌標的であるSTAT3阻害剤の獲得を目指して、膜透過ユニットcisNfCfを導入した環状ペプチドを種々合成し、膜透過性を確認するとともに、STAT3阻害活性の初期的評価を実施した。課題3. 三次元多様型RaPIDシステムの構築と応用に関する研究においては、ホスホグリセリン酸異性化酵素に対する強力な阻害剤を見出した。課題 4. ネガマイシン（NM）をプロトタイプとするリードスルー誘起分子の創出研究においては、シクロプロパンユニットを導入した 3-エピデオキシNM誘導体を種々合成し、リードスルー誘起活性を評価した。課題 5. シクロプロパンを配座制御素子とする新規機能性核酸の創出研究においては、シクロプロパンヌクレオシドを大量合成し、それを組み込んだオリゴヌクレオチドを合成した。
日本学術振興会, 基盤研究(A), 北海道大学, Coinvestigator, Competitive research funding, 19H01014

Development of a new foldamer as a mimetic of alfa-helix
Grants-in-Aid for Scientific Research
Apr. 2017 - Mar. 2019
WATANABE Mizuki
I designed of optically active cyclopropane δ-amino acid oligomers wth various stereochemistries and calculated their most stable conformation using MacroModel. As a result, a homo-oligomers of specific stereoisomer of an optically active cyclopropane δ-amino acid form stable, right-handed helix. Then, I synthesized the optically active cyclopropane δ-amino acid monomer from the optically active glycidol via a stereoselective Grignard reaction and an asymmetric alkylation using asymmetric auxiliary groups in 18 steps. After oligomerization to various lengths, CD measurement, NMR measurement, and X-ray crystal structure analysis of the three-dimensional structure were performed. As a result, it was found that a hexameric or higher oligomer forms a helical secondary structure as calculated.
Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists (B), Hokkaido University, Principal investigator, Competitive research funding, 17K15476

Analysis of regulation of lipid metabolism by vitamin D metabolite
Grants-in-Aid for Scientific Research
Apr. 2014 - Mar. 2017
WATANABE Mizuki
This study revealed that an endogenous vitamin D metabolite suppresses the lipid biosynthesis. Sterol regulatory element-binding proteins (SREBPs) are transcription factors that control lipid homeostasis. We screened a chemical library of endogenous molecules and identified 25-hydroxyvitamin D (25OHD) as an inhibitor of SREBP activation. Unlike sterols and other SREBP inhibitors, 25OHD impairs SREBP activation by inducing proteolytic processing and ubiquitin-mediated degradation of SCAP, thereby decreasing SREBP levels independently of the vitamin D receptor. Vitamin D supplementation has been proposed to reduce the risk of metabolic diseases, but the mechanisms are unknown. The present results suggest a previously unrecognized molecular mechanism of vitamin D-mediated lipid control that might be useful in the treatment of metabolic diseases.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Principal investigator, 26350972

Development of synthetic small molecules that control the lipid biosynthesis
Grants-in-Aid for Scientific Research
Apr. 2012 - Mar. 2014
WATANABE Mizuki
Various small molecules based on the structure of "fatostatin", which was a synthetic molecule identified by our research group that inhibits a lipid biosynthetic pathway, were designed and synthesized. The inhibitory effects of these synthesized molecules on the important protein for the lipid biosynthesis were evaluated by the cell-based reporter assay. As a result, a new small molecule that shows more potent inhibitory effects on the lipid biosynthesis pathway than previous ones was obtained. Now, its detail function in cells are investigated.
Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists (B), Kyoto University, Principal investigator, 24710260

シクロプロパンの構造特性を活用した配座制御型分子設計による医薬分子の創製研究
科学研究費助成事業
2008 - 2009
渡邉 瑞貴
医薬分子を効率的・合理的に創出するためには、三次元的多様性を有する一連の配座制御型化合物群を設計・合成し、三次元的構造活性相関を検討することが有効と推論した。この方法は、標的分子にサブタイプが存在し、その中のあるサブタイプに選択的に作用するリガンドを見出す場合に特に有効と考えられる。これを実験的に検証する目的で、アルギニンを基質としてセカンドメッセンジャーである一酸化窒素(NO)を合成する酵素NOS(nitric oxide synthase)を標的とする創薬研究を企画した。そこで、配座制御素子として独自に開発したシクロプロパンユニットを用いて、三次元的多様性を特徴とする一連のNOSの基質であるアルギニンの配座制限誘導体を設計した。NOSには3つのサブタイプの存在が知られているが、この中で中枢に局在するnNOS阻害剤はアルツハイマー病等の神経疾患治療薬、一方、誘導型のiNosがリュウマチ等の炎症性疾患の治療薬になることが期待されており、これらの選択的阻害薬が見出されることを期待した。
既に合成法を確立している光学活性cis-及びtrans-シクロプロパンユニットをシントンとして、目的物の合成を進めることにた。合成上の鍵はシクロプロパン側鎖上にα-アミノ酸構造を立体選択的に構築できるか否かであったが、光学活性なtert-ブタンスルフィナミドを不斉補助としてもちいるGrignard反応によりその構築に成功した。その後、側鎖の増炭、グナニジニル基の導入等を経て目的とする8種類のアルギニン配座制限誘導体を合成することに成功した。現在、これらの生物活性を検討中である。
日本学術振興会, 若手研究(スタートアップ), 北海道大学, Principal investigator, 20890002

ビタミンD3誘導体及びその薬学的用途
Patent right, 渡邉 瑞貴; 浅野 理沙; 長澤 和夫; 上杉 志成, 国立大学法人京都大学, 国立大学法人東京農工大学
特願2017-534365, 24 Dec. 2015
特表2018-502100, 25 Jan. 2018
201803020170725669

代謝並びに体重関連疾患の処置のための組成物および方法
Patent right, 上杉 志成; ワキル,サリフ,ジェイ; アブ-エルヘイガ,ルトフィ; 渡邉 瑞貴, ベイラー カレッジ オブ メディスン
特願2016-537878, 29 Aug. 2014
特表2016-534124, 04 Nov. 2016
201703019506803340

模擬講義「クスリのカタチ 〜三次元の姿〜」
03 Aug. 2025
Lecturer
北海道大学オープンキャンパス2025

模擬講義「クスリのカタチ 〜三次元の姿〜」
04 Aug. 2024
Lecturer
北海道大学 オープンキャンパス2024

模擬講義「クスリのカタチ 〜”三次元“の姿〜」
06 Aug. 2023
Lecturer
北海道大学オープンキャンパス2023

模擬講義「クスリのカタチ 〜”三次元“の姿〜」
07 Aug. 2022
Lecturer
北海道大学 オープンキャンパス2022
Schoolchildren, Junior high school students, High school students