九州大学-研究者情報 [平井剛 (教授) 薬学研究院創薬科学部門]

植物酸化ステロイドを起点とした生物活性分子創製
キーワード：酸化ステロイド、有機合成化学、分子設計、NF-kB活性化抑制、作用機序
2006.04.

代謝耐性型複合糖質（糖脂質）の創製
キーワード：複合糖質、糖脂質、分子設計、有機合成、生物機能評価
2005.04.

天然物や複合糖質のケミカルバイオロジーに貢献する新しい分子ツール創製
キーワード：分子設計、有機合成、ケミカルバイオロジー
2010.04.

天然物を基盤とする新規生物活性分子創製研究
キーワード：天然物、分子設計、有機合成、活性評価
2002.04.

国立研究開発法人日本医療研究開発機構　革新的先端研究開発支援事業「画期的医薬品等の創出をめざす脂質の生理活性と機能の解明」
2016.10～2020.03, 代表者：横山信治, 中部大学次世代食育研究センター.

新学術領域研究「反応集積化が導く中分⼦戦略：⾼次⽣物機能分⼦の創製」
2016.04～2020.03, 代表者：深瀬浩一, 大阪大学大学院理学研究科.

主要著書

1.	平井剛, 日本化学会編：生体分子反応を制御する（CSカレントレビュー 36）：化学的手法による機構と反応場の解明, 化学同人, 研究最前線　第16章　複合糖質の反応場を探る：代謝耐性型アナログと光親和性標識法（p145-152）, 2020.04.

主要原著論文

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1.	Yu Hidaka, Noriaki Kiya, Makoto Yoritate, Kazuteru Usui, Go Hirai, Synthesis of CH2-linked alpha-galactosylceramide and its glucose analogues through glycosyl radical-mediated direct C-glycosylation, Chemical Communications, 10.1039/d0cc00785d, 56, 34, 4712-4715, 2020.04, [URL], We describe a new synthetic approach for C-linked glycolipid analogues, in which the cleavable O-glycosidic linkage is replaced by a carbon unit. Direct C-glycosylation of a conformationally constrained and stable C1-sp3 hybridized xanthate carbohydrate with carefully designed sphingosine units afforded the CH2-linked analogue of antitumor-active KRN7000 and its glucose congener..
2.	Yusaku Nomura, Frédéric Thuaud, Daisuke Sekine, Akihiro Ito, Satoko Maeda, Hiroyuki Koshino, Daisuke Hashizume, Atsuya Muranaka, Thomas Cruchter, Masanobu Uchiyama, Satoshi Ichikawa, Akira Matsuda, Minoru Yoshida, Go Hirai, Mikiko Sodeoka, Synthesis of All Stereoisomers of Monomeric Spectomycin A1/A2 and Evaluation of Their Protein SUMOylation-Inhibitory Activity, Chemistry - A European Journal, 10.1002/chem.201901093, 25, 35, 8387-8392, 2019.06, [URL], A synthetic methodology to access all possible stereoisomers of spectomycin A1 (SMA1) and A2 (SMA2) has been established through late-stage diversification. The key reaction for the construction of all four diastereomers is an intramolecular cyclization based on the umpolung of π-allyl palladium species with bis(pinacolato)diborane (B₂(pin)₂). Silyl group assisted direct benzylic oxidation of each isomer enabled construction of the fragile β-hydroxytetralone skeleton to provide the SMAs. The relative and absolute stereochemistry of SMA2 was also determined, and the absolute stereochemistry of SMA1 was extrapolated based on the optical rotation of SMA2. The axial chirality of SMAs is discussed based on circular dichroism spectra and DFT calculations, and it is concluded that the M isomer is predominant in solution. Biochemical assessment of all isomers in vitro revealed that the C9 hydroxyl group and dimeric structure were both important for protein SUMOylation-inhibitory activity..
3.	Yu Mikame, Kazuko Yoshida, Daisuke Hashizume, Go Hirai, Kazuo Nagasawa, Hiroyuki Osada, Mikiko Sodeoka, Synthesis of All Stereoisomers of RK460 and Evaluation of Their Activity and Selectivity as Abscisic Acid Receptor Antagonists, Chemistry - A European Journal, 10.1002/chem.201806056, 25, 14, 3496-3500, 2019.03, [URL], The PYR/PYL/RCAR protein families have recently emerged as receptors of the phytohormone abscisic acid (ABA, 1), which regulates plant responses to environmental stress. These families have multiple members with different physiological actions, and so selective agonists or antagonists are needed both as tools to elucidate functional differences and as lead compounds for agrochemicals. We previously identified RK460 (rac-3 a) as a PYR1-selective antagonist, and showed that it possesses five stereocenters on a 6,5-cis-bicyclo skeleton. Here, we synthesized all the stereoisomers of RK460 and evaluated their activity towards a panel of receptors. Relative stereochemistry as well as absolute stereochemistry was important for selective action..
4.	Noriaki Kiya, Yu Hidaka, Kazuteru Usui, Go Hirai, Synthesis of CH₂-Linked α(1,6)-Disaccharide Analogues by α-Selective Radical Coupling C-Glycosylation, Organic Letters, 10.1021/acs.orglett.9b00133, 21, 6, 1588-1592, 2019.03, [URL], C-Linked carbohydrate structure, in which the cleavable O-glycosidic linkage is replaced by a carbon unit, is a useful tool for functional analyses of glycoconjugates. We describe a synthetic method for α-CH₂-linked disaccharide structures, such as Glc(1,6)-Glc, by stereoselective radical-coupling C-glycosylation between a conformationally constrained and stable C1-sp³ hybridized xanthate donor and a carefully designed acceptor..
5.	Eisuke Ota, Kazuteru Usui, Kana Oonuma, Hiroyuki Koshino, Shigeru Nishiyama, Go Hirai, Mikiko Sodeoka, Thienyl-Substituted α-Ketoamide A Less Hydrophobic Reactive Group for Photo-Affinity Labeling, ACS Chemical Biology, 10.1021/acschembio.7b00988, 13, 4, 876-880, 2018.02, [URL], Photoaffinity labeling (PAL) is an important tool in chemical biology research, but application of α-ketoamides for PAL has been hampered by their photoinstability. Here, we show that 2-thienyl-substituted α-ketoamide is a superior photoreactive group for PAL. Studies with a series of synthetic mannose-conjugated α-ketoamides revealed that 2-thienyl substitution of α-ketoamide decreased the electrophilicity of the keto group and reduced the rate of photodegradation. Mannose-conjugated thienyl α-ketoamide showed greater concanavalin A labeling efficiency than other alkyl or phenyl-substituted α-ketoamides. In comparison with representative conventional photoreactive groups, 2-thienyl ketoamide showed reduced labeling of nontarget proteins, probably owing to its lower hydrophobicity..
6.	Morita Masaki, Shuntaro Kojima, Megumi Ohkubo, Hiroyuki Koshino, Daisuke Hashizume, Go Hirai, Keiji Maruoka, Mikiko Sodeoka, Synthesis of the Right-Side Structure of Type B Physalins, ISRAEL JOURNAL OF CHEMISTRY, 10.1002/ijch.201600110, 57, 309-318, 2017.04.
7.	Qianqian Wang, Yuta Kuramoto, Yozo Okazaki, Eisuke Ota, Masaki Morita, Go Hirai, Kazuki Saito, Mikiko Sodeoka, Synthesis of polyunsaturated fatty acid-containing glucuronosyl-diacylglycerol through direct glycosylation, Tetrahedron Letters, 10.1016/j.tetlet.2017.06.034, 58, 30, 2915-2918, 2017.01, [URL], We describe a total synthesis of a polyunsaturated fatty acid (PUFA)-containing glucuronosyldiacylglycerol (GlcADG), which is a surrogate glycolipid whose synthesis is remarkably upregulated in plant membranes under phosphorus-depleted conditions. Glycosylation between the glucuronide donor bearing 3,4-dimethoxybenzyl (DMPM) protecting groups and di-acylglycerol acceptor proceeded smoothly in the presence of gold(I) catalyst to provide the protected α-isomer of GlcADG as the major product..
8.	Xiaoying Sun, Go Hirai, Masashi Ueki, Hiroshi Hirota, Qianqian Wang, Yayoi Hongo, Takemichi Nakamura, Yuki Hitora, Hidekazu Takahashi, Mikiko Sodeoka, Hiroyuki Osada, Makiko Hamamoto, Minoru Yoshida, Yoko Yashiroda, Identification of novel secreted fatty acids that regulate nitrogen catabolite repression in fission yeast, Scientific Reports, 10.1038/srep20856, 6, 20856, 2016.02.
9.	Eisuke Ota, Yu Mikame, Go Hirai, Shigeru Nishiyama, Mikiko Sodeoka, Photochemical and Additive-Free Coupling Reaction of α-Cumyl α-Keto Esters via Intermolecular C–H Bond Activation, SYNLETT, 10.1055/s-0035-1561098, 27, 1128-1132, 2016.01.
10.	Eisuke Ota, Yu Mikame, Go Hirai, Hiroyuki Koshino, Shigeru Nishiyama, Mikiko Sodeoka, Photo-induced formation of cyclopropanols from α-ketoamides via γ-C-H bond activation, Tetrahedron Lett., 10.1016/j.tetlet.2015.09.038, 56, 5991-5994, 2015.09.
11.	Masaaki Ozawa, Masaki Morita, Go Hirai, Satoru Tamura, Masao Kawai, Ayako Tsuchiya, Kana Oonuma, Keiji Maruoka, and Mikiko Sodeoka, Contribution of Cage-Shaped Structure of Physalins to Their Mode of Action in Inhibition of NF-kB Action, ACS Med. Chem. Lett. , 10.1021/ml400144e, 4, 730-735, 2013.06.
12.	Ayako Tsuchiya, Miwako Asanuma, Go Hirai, Kana Oonuma, Muhammad Muddassar, Eri Nishizawa, Yusuke Koyama, Yuko Otani, Kam Y. J. Zhang, and Mikiko Sodeoka, CDC25A-inhibitory RE Derivatives Bind to Pocket Adjacent to the Catalytic Site, Mol. BioSyst., 10.1039/C3MB00003F, 9, 1026-1034, 2013.02.
13.	Masaki Morita, Go Hirai, Meguni Ohkubo Hiroyuki koshino, Daisuke Hashizume, Keiji Maruoka, and Mikiko Sodeoka, Kinetically Controlled One-Pot Formation of DEFGH-Rings of Type B Physalins through Domino-Type Transformations, Org, Lett., 14, 3434-3437, 2012.06.
14.	Ayako Tsuchiya, Go Hirai, Yusuke Koyama, Kana Oonuma, Yuko Otani, Hiroyuki Osada, and Mikiko Sodeoka, Dual-specificity Protein Phosphatase CDC25A/B Inhibitor Identified from a Focused Library with Non-electrophilic Enamine Core Structure, ACS Med. Chem. Lett. , 10.1021/ml2002778, 3, 264-298, 2012.02.
15.	Go Hirai, Ayako Tsuchiya, Yusuke Koyama, Yuko Otani, Kana Oonuma, Kosuke Dodo, Siro Simizu, Hiroyuki Osada, and Mikiko Sodeoka, Development of a Vaccinia H1-Related (VHR) Phosphatase Inhibitor with NonAcidic Phosphate-Mimicking Core Structure, ChemMedChem, 10.1002/cmdc.201100107, 6, 617-622, 2011.03.
16.	Megumi Ohkubo, Go Hirai, Mikiko Sodeoka, Synthesis of the DFGH ring system of Type B Physalins: Highly Oxygenated, Cage-Shaped Molecules, Angew. Chem. Int. Ed., 10.1002/anie.200900634, 48, 3862-3866, 2009.04.
17.	Isao Fukuda, Akihiro Ito, Go Hirai, Shinichi Nishimura, Hisashi Kawasaki, Hisato Saitoh, Ken-ichi Kimura, Mikiko Sodeoka, Minoru Yoshida, Ginkgolic Acid Inhibits Protein SUMOylation by Blocking Formation of the E1-SUMO Intermediate, Chemistry & Biology, 10.1016/j.chembiol.2009.01.009, 16, 133-140, 2009.02.
18.	Toru Watanabe, Go Hirai, Marie Kato, Daisuke Hashizume, Taeko Miyagi, and Mikiko Sodeoka, Synthesis of CH2-Linked α(2,3)Sialylgalactose Analogue: On the Stereoselectivity of the Key Ireland-Claisen Rearrangement, Org. Lett., 10.1021/ol801519j, 10, 4167-4170, 2008.09.
19.	Go Hirai, Toru Watanabe, Kazunori Yamaguchi, Taeko Miyagi, and Mikiko Sodeoka, Stereocontrolled and Convergent Entry to CF2-Sialosides: Synthesis of CF2-Linked Ganglioside GM4, J. Am. Chem. Soc., 10.1021/ja075738w, 129, 15420-15421, 2007.11.

主要総説, 論評, 解説, 書評, 報告書等

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1.	平井　剛, 新たな光反応性基で拡がる光親和性標識法のポテンシャル, ファルマシア, 10.14894/faruawpsj.54.10_953, 2018.10.
2.	平井剛, 淺沼三和子, 土屋綾子, 袖岡幹子, 目的志向型ライブラリー戦略による両特異性プロテインホスファターゼ阻害剤の開発：コア構造の改変とユニークな阻害メカニズム, 有機合成化学協会誌, Vol.74, Page 532-540, 2016.05, Synthesis of a focused library (FL) is an efficient method to develop novel compounds regulating functions of specific enzymes. Compounds in a FL are composed of a common core structure with different building blocks. Herein, our design and synthesis of FLs based on selective inhibitors of dual-specificity protein phosphatases (DSPs) is summarized. A first generation FL having an acidic core structure extracted from a natural product, RK-682, does not contain a highly selective inhibitor for DSPs, and showed very weak activity at the cellular level, possibly due to poor cell membrane permeability. Upon building the second FL, the property of the core structure was modified from acidic to neutral. Construction of a second-generation FL (RE derivatives) having the enamine derivative of 3-acyltetronic acid as the core structure resulted in dramatic improvement of cell membrane permeability and inhibitory selectivity. As a result, VHR-selective RE12 and CDC25A/B-selective RE44 were discovered. Replacement of the side chain in RE12 afforded RE176, which showed more potent anti-proliferative activity against HeLa cells. Core structure modification from acidic to neutral also changed the mode of action of inhibitors. RE derivatives showed a non-competitive inhibition profile and interacts with a pocket adjacent to the active site of CDC25s..
3.	平井剛, 分子設計と有機合成による高機能型生物活性分子の創製：Physalin類のかご型構造の合成と生物機能, 有機合成化学協会誌.
4.	Go Hirai, Mimicking/Extracting Structure and Functions of Natural Products: Synthetic Approaches that Address Unexplored Needs in Chemical Biology, The Chemical Record (Personal Account).
5.	Go Hirai, Mikiko Sodeoka, Focused Library with a Core Structure Extracted from Natural Products and Modified: Application to Phosphatase Inhibitors and Several Biochemical Findings, Acc. Chem. Res..
6.	Go Hirai, Eisuke Ota, Motonari Sakai, Shigeru Nishiyama, Mikiko Sodeoka, C-Sialosides: Synthesis and Biological Activities（C-シアロシド結合を有する糖鎖アナログ：その合成と利用価値）, Trends in glycoscience and glycotechnology (Minireview).

主要学会発表等

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1.	Go Hirai, Glycan probes: C-glycosides and photo-affinity probes, ACGG11, 2019.11.
2.	Go Hirai, Thienyl‐substituted α‐ketoamide: a less hydrophobic photoreactive group useful for analysis of carbohydrate‐protein interaction, European Carbohydrate Symposium (EurocarboXX), 2019.07.
3.	平井剛, 擬天然物を標的とする有機合成, 第56回化学関連支部合同九州大会, 2019.07.
4.	平井剛, 有機合成で新しいケミカルバイオロジーツールを創る, 2019年度前期（春季）有機合成化学講習会　「新時代に飛躍する有機合成化学―機能性分子、材料から創薬まで―」, 2019.06.
5.	平井剛, 複合糖質を高機能化する有機化学, 大塚創薬化学シンポジウム2018, 2018.11.
6.	平井剛, Thienyl-Substituted α-Ketoamide: a Less Hydrophobic Photoreactive Group, The Third A3 Roundtable Meeting on Chemical Probe Research Hub, 2018.11.
7.	平井剛, 天然物改変型創薬研究, 第12回九州薬科学研究教育連合主催合宿研修, 2018.07.
8.	平井剛, 合成化学が拓く生物活性物質創製研究, 生体機能関連化学部会若手の会　第30回サマースクール, 2018.07.
9.	平井剛, 糖鎖に細工をする有機化学, 有機合成化学協会東海支部主催　平成30年度有機合成セミナー, 2018.06.
10.	平井剛, 有機化学で複合糖質研究に挑む, 第29回万有仙台シンポジウム　未来を指向した有機合成化学, 2018.06.
11.	平井剛, 天然物を高機能化する有機合成, 日本化学会第98春季年会(2018)：天然有機化合物の全合成：効率的分子構築のための新しい反応と戦略（CSJカレントレビュー企画）, 2018.03.
12.	平井剛, Focused Libraryのススメ, Asian Chemical Probe Research Hub Symposium：天然物有機化学・天然物合成とケミカルバイオロジー, 2018.02.
13.	平井剛, 非天然型複合糖質を創る, 糸状菌分子生物学研究会　第5回若手の会 WS in SAGA, 2017.11.
14.	平井剛, 人工糖鎖を備えて未来の疾患と戦う, 第7回CSJ化学フェスタ2017「10年後にはどんな分子ができる？有機合成化学者の「革命分子」への挑戦」 (2017.10.18), 2017.10.
15.	Go Hirai, Synthesis of Natural Product Compartments for Finding Their Functions, The 3rd HU-TMU-KU Joint Symposium for Pharmaceutical Sciences, 2017.09.
16.	平井剛, 有機合成化学を起点とするケミカルバイオロジー研究, 平成29年度有機合成化学講演会　－合成有機化学のフロンティア－, 2017.06.
17.	平井剛, 有機化学を起点とするケミカルバイオロジー研究, 徳島大学大学院「創薬先端合成化学特論」講演会, 2017.05.
18.	平井剛, 代謝に着目した中分子糖鎖分子の設計と機能, 日本薬学会第137年会一般シンポジウム「中分子創薬研究のフロンティア－反応集積化が導く中分子戦略：高次生物機能分子の創製－, 2017.03.
19.	平井剛, 代謝に着目した中分子糖鎖分子の設計と機能, 日本薬学会第137年会一般シンポジウム「中分子創薬研究のフロンティア－反応集積化が導く中分子戦略：高次生物機能分子の創製－, 2017.03.
20.	Go Hirai, Synthesis of Monomers for Spectomycin B1, A Middle Size SUMOylation Inhibitor Molecule, 7th CCS/CSJ Young Chemist Forum, 2017.03.
21.	Go Hirai, Synthesis of Monomers for Spectomycin B1, A Middle Size SUMOylation Inhibitor Molecule, 7th CCS/CSJ Young Chemist Forum（第7回日中若手化学者フォーラム）, 2017.03.
22.	平井剛, 高機能性複合糖質の創製, 日本化学会中国四国支部地区化学講演会「有機化学者による生命科学へのアプローチ」, 2016.12.

特許出願・取得

特許出願件数 2件

特許登録件数 0件

所属学会名

日本ケミカルバイオロジー学会

日本糖質学会

有機合成化学協会

日本化学会

日本薬学会

学協会役員等への就任

2019.01～2022.01, 日本薬学会医薬化学部会, 常任世話人.

学会大会・会議・シンポジウム等における役割

2018.10.30～2018.11.23, The Third A3 Roundtable Meeting on Chemical Probe Research Hub, Chairperson.

2019.03.20～2019.03.23, 日本薬学会第139年会, 座長.

2018.11.17～2018.11.18, 第35回日本薬学会九州支部大会, 組織委員会.

2018.09.26～2018.09.28, 第60回天然有機化合物討論会, 組織委員会および座長.

2018.06.21～2018.06.22, 創薬懇話会2018 in 志賀島, 事務局.

2017.09.20～2017.09.22, 第59回天然有機化合物討論会, 座長（Chairmanship）.

2018.03.25～2017.03.28, 日本薬学会第138年会, 座長（Chairmanship）.

2017.03.24～2017.03.27, 日本薬学会第137年会, 座長（Chairmanship）.

2017.03.18, 7th CCS/CSJ Young Chemist Forum, 座長（Chairmanship）.

2017.03.16～2017.03.19, 日本化学会第97春季年会, 座長（Chairmanship）.

2016.09.14～2016.09.16, 第58回天然有機化合物討論会, 座長（Chairmanship）.

2013.12～2014.12, 日本化学会年会, プログラム編成委員.

2014.01～2016.01, 有機合成化学協会, 事業委員会委員.

学会誌・雑誌・著書の編集への参加状況

2018.04～2021.03, Chemical and Pharmaceutical Bulletin, 国際, 編集委員.

2015.12～2018.03, 天然有機化合物の全合成:独創的なものづくりの反応と戦略 (CSJカレントレビュー), 国内, 編集委員.

2013.01～2015.01, 有機合成化学協会誌, 国内, 編集委員.

2011.03～2013.03, 有機合成化学協会誌, 国内, 編集協力委員.

学術論文等の審査

年度	外国語雑誌査読論文数	日本語雑誌査読論文数	国際会議録査読論文数	国内会議録査読論文数	合計
2019年度	10				10
2018年度	9				9
2017年度	14				14
2016年度	16	0	0	0	16

長瀬振興研究奨励賞, 公益財団法人長瀬科学技術振興財団, 2017.04.

Thieme Chemistry Journal Award 2015, Thieme Chemistry - Georg Thieme Verlag, 2014.11.

GLYCOTOKYO2014奨励賞, GLYCOTOKYO, 2014.11.

2013年度有機合成化学奨励賞, 有機合成化学協会, 2014.02.

Asian Core Program Lectureship Award, The 5th International Conference on Cutting-Edge Organic Chemistry in Asia /The 1st New Phase International Conference on Cutting-Edge Organic Chemistry in Asia, 2010.11.

第54回日本薬学会関東支部大会奨励賞, 日本薬学会関東支部, 2010.10.

第22回（2009年度）有機合成化学協会「セントラル硝子研究企画賞」, 有機合成化学協会, 2010.02.

科学研究費補助金の採択状況(文部科学省、日本学術振興会)

2018年度～2021年度, 基盤研究(B), 代表, 多糖型シアリダーゼ阻害剤開発のための合成化学基盤.

2018年度～2019年度, 新学術領域研究, 代表, 代謝安定型糖鎖を基盤とする高次生物機能中分子複合糖質アナログ創製.

2016年度～2017年度, 新学術領域研究, 代表, 代謝安定型糖鎖を基盤とする高次生物機能複合糖質アナログの創製.

2015年度～2017年度, 挑戦的萌芽研究, 代表, 糖鎖の生体内代謝を追跡する革新的分子プローブの開発.

2014年度～2015年度, 新学術領域研究, 代表, 酸化ステロイドの鍵構造アナログ創製と作用機序解析.

2013年度～2014年度, 新学術領域研究, 代表, タンパク質ＳＵＭＯ化を阻害する天然物リガンドの合成供給と構造活性相関.

2010年度～2012年度, 基盤研究(C), 代表, ホオズキ成分physalin類の標的タンパク質同定に向けた有機合成化学的展開.

2007年度～2008年度, 若手研究(B), 代表, ホスファターゼプロファイリングを志向した新規共有結合型阻害剤の創製.

2004年度～2005年度, 若手研究(B), 代表, プロテインキナーゼC活性化機構の解明と新規阻害剤の開発.

競争的資金(受託研究を含む)の採択状況

2016年度～2019年度, 国立研究開発法人日本医療研究開発機構　革新的先端研究開発支援事業（PRIME）　画期的医薬品等の創出をめざす脂質の生理活性と機能の解明, 代表, 糖脂質の代謝と分子相互作用を解明する分子ツール創製.

寄附金の受入状況

2019年度, 公益財団法人内藤記念科学振興財団　内藤記念科学奨励金・研究助成.

2018年度, 公益財団法人柿原科学技術研究財団　科学技術研究助成.

2018年度, 公益財団法人武田科学振興財団　薬学系研究助成.

2017年度, 公益財団法人上原記念生命科学財団　研究推進特別奨励金.

2017年度, 公益財団法人長瀬科学技術振興財団　助成金.

2016年度, 公益財団法人東京生化学研究会.


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