Design of a stabilized short helical peptide and its application

• Project/Area Number: 22590114
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: National Institute of Health Sciences
• Principal Investigator: KURIHARA Masaaki 国立医薬品食品衛生研究所, 有機化学部, 部長 (20205206)
• Co-Investigator(Renkei-kenkyūsha): DEMIZU Yosuke 国立医薬品食品衛生研究所, 有機化学部 (90389180)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2010: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: ヘリカルペプチド / 核内レセプター / コアクチベータ / ペプチド / ヘリックス / ビタミンＤレセプター / 転写阻害 / ビタミンDレセプター

Research Abstract

We synthesized stapled helical leucine-based peptides containing 2-aminoisobutyric acid and a covalent cross-linked unit as inhibitors of vitamin D receptor (VDR)-coactivator interactions. The effects of these peptides on the human VDR were examined in an inhibition assay based on the receptor cofactor assay system, and one of them, exhibited potent inhibitory activity.

Research Products

• [Journal Article] (2013)
  • Author(s): Y. Demizu, S. Nagoya, M. Shirakawa, M. Kawamura, N. Yamagata, Y. Sato, M. Doi, M. Kurihara
  • Journal Title: Bioorg. Med. Chem. Lett Volume: 23
  • URL: http://www.sciencedirect.com/science/article/pii/S0960894X13007099
  • Peer Reviewed
• [Journal Article] Design and synthesis of estrogen receptor degradation inducer based on a protein knockdown strategy (2012)
  • Author(s): Y. Demizu, K. Okuhira, H. Motoi, A. Ohno, T. Shoda, K. Fukuhara, H. Okuda, M. Naito, M. Kurihara
  • Journal Title: Bioorg. Med. Chem. Lett Volume: 22 Pages: 1793-1796
  • Peer Reviewed
• [Journal Article] Conformations of helical Aib peptides containinga pair of L-amino acid and D-amino acid (2012)
  • Author(s): Y. Demizu, Y. Yabuki, M. Doi, Y. Sato,M. Tanaka, M. Kurihara
  • Journal Title: J. Pept. Sci Volume: 18 Issue: 7 Pages: 466-475
  • DOI: 10.1002/psc.2418
  • Peer Reviewed
• [Journal Article] Twisted Structure of a Cyclic Hexapeptide Containing a Combination of Alternating L-Leu-D-Leu- Aib Segments (2012)
  • Author(s): Demizu, Y., Nagoya, S., Doi, M., Sato, Y., Tanaka, M., Kurihara, M
  • Journal Title: J. Org. Chem Volume: 77 Pages: 9361-9365
  • Peer Reviewed
• [Journal Article] Helical structures of bicyclic -amino acid homo-chiral oligomers with the chiral centers at the side-chain fused-ring junctions (2012)
  • Author(s): K. Anan.
  • Journal Title: Helv. Chim. Acta. Volume: 95 Pages: 1694-1713
  • Peer Reviewed
• [Journal Article] Solid-phase nucleophilic fluorination (2012)
  • Author(s): Y. Demizu
  • Journal Title: Synth. Commun. Volume: 42 Pages: 1724-1730
  • Peer Reviewed
• [Journal Article] One-Handed Helical Screw Direction of Homopeptide Foldamer Exclusively Induced by Cyclic α-Amino Acid Side-Chain Chiral Centers (2012)
  • Author(s): Y.Demizu
  • Journal Title: Chem.Eur.J. Volume: 18 Pages: 2430-2439
  • Peer Reviewed
• [Journal Article] Design and synthesis of estrogen receptor degradation inducer based on a protein knockdown strategy (2012)
  • Author(s): Y.Demizu
  • Journal Title: Bioorg.Med.Chem.Lett Volume: 22 Pages: 1793-1796
  • Peer Reviewed
• [Journal Article] Design of a stabilized short helical peptide and its application to catalytic enantioselective epoxidation of (E)-chalcone (2011)
  • Author(s): Yamagata, N., Demizu, Y., Sato, Y., Doi, M., Tanaka, M., Nagasawa, K., Okuda, H., Kurihara, M
  • Journal Title: Tetrahedron Letters Volume: 52 Pages: 798-801
  • Peer Reviewed
• [Journal Article] Enantioselective epoxidation of α,β-unsaturated ketones catalyzed by stapled helical L-Leu-based peptides (2011)
  • Author(s): Y. Demizu, N. Yamagata, S. Nagoya, Y. Sato, M. Doi, M. Tanaka, K. Nagasawa, H. Okuda, M. Kurihara
  • Journal Title: Tetrahedron Volume: 67 Pages: 6155-6165
  • Peer Reviewed
• [Journal Article] Screw-Sense Control of Helical Oligopeptides Containing Equal Amounts of l- and d-Amino Acids (2011)
  • Author(s): Y. Demizu, M. Doi, M. Tanaka, H. Okuda, M. Kurihara
  • Journal Title: Chem. Eur. J., Volume: 17 Pages: 11107-11109
  • Peer Reviewed
• [Journal Article] Effect of one D-Leu residue on right-handed helical -L-Leu-Aibpeptides in the crystal state (2011)
  • Author(s): Y. Demizu, M. Doi, Y. Sato, M. Tanaka, H. Okuda, M. Kurihara
  • Journal Title: J. Pept. Sci Volume: 17 Pages: 420-426
  • Peer Reviewed
• [Journal Article] β-PNA : Peptide nucleic acid (PNA) with a chiral center at the β-position of the PNA backbone (2011)
  • Author(s): T.Sugiyama
  • Journal Title: Bioorg.Med.Chem.Lett. Volume: 21 Pages: 7317-7320
  • Peer Reviewed
• [Journal Article] Effect of one D-Leu residue on right-handed helical-L-Leu-Aib-peptides in the crystal state (2011)
  • Author(s): Y.Demizu
  • Journal Title: J.Pept.Sci. Volume: 17 Pages: 420-426
  • Peer Reviewed
• [Journal Article] Identification of Mutaprodenafil in a Dietary Supplement and its Subsequent Synthesis (2011)
  • Author(s): Y.Demizu
  • Journal Title: Chem.Pharm.Bull. Volume: 59 Pages: 1314-1316
  • NAID: 130001087104
  • Peer Reviewed
• [Journal Article] Design, synthesis and X-ray crystallographic study of new nonsecosteroidal vitamin D receptor ligands (2011)
  • Author(s): Y.Demizu
  • Journal Title: Bioorg.Med.Chem.Lett. Volume: 21 Pages: 6104-6107
  • Peer Reviewed
• [Journal Article] Screw-Sense Control of Helical Oligopeptides Containing Equal Amounts of l-and d-Amino Acids (2011)
  • Author(s): Y.Demiz
  • Journal Title: Chem.Eur.J. Volume: 17 Pages: 11107-11109
  • Peer Reviewed
• [Journal Article] Conformational studies on peptides containing α,α-disubstituted α-amino acids : chiral cyclic α,α-dsubstituted α-amino acid as an α-helical inducer (2011)
  • Author(s): Y.Demizu
  • Journal Title: Org.Biomol.Chem. Volume: 9 Pages: 3303-3312
  • Peer Reviewed
• [Journal Article] Design of a stabilized short helical peptide and its application to catalytic enantioselective epoxidation of (E)-chalcone (2011)
  • Author(s): N.Yamagata
  • Journal Title: Tetrahedron Letters Volume: 52 Pages: 789-801
  • Peer Reviewed
• [Journal Article] Facile synthesis of stereoisomers of the non-secosteroidal ligand LG190178 and their evaluation using the mutant vitamin D receptor (2011)
  • Author(s): Y.Demizu
  • Journal Title: Lett.Org.Chem. Volume: 8 Pages: 43-47
  • Peer Reviewed
• [Journal Article] Design of a stabilized short helical peptide and its application to catalytic enantioselective epoxidation of(E)-chalcone (2011)
  • Author(s): N.Yamagata
  • Journal Title: Tetrahedron Lett. Volume: 52 Pages: 798-801
  • Peer Reviewed
• [Journal Article] Facile synthesis of stereoisomers of the non-secosteroidal ligand LG190178 and their evaluation using the mutant vitamin D receptor (2011)
  • Author(s): Demizu, Y.
  • Journal Title: Lett.Org.Chem Volume: 8 Pages: 43-47
  • Peer Reviewed
• [Journal Article] Controlling the helical screw sense of peptides with C-terminal L-valine (2010)
  • Author(s): Demizu, Y., Yamagata, N., Sato, Y., Doi, M., Tanaka, M., Okuda, H., Kurihara, M
  • Journal Title: J. Pept. Sci. Volume: 16 Pages: 153-158
  • Peer Reviewed
• [Journal Article] Three-Dimensional Structural Control of Diastereomeric Leu-Leu-Aib-Leu-Leu-Aib Sequences in the Solid State (2010)
  • Author(s): Demizu, Y., Doi, M., Sato, Y., Tanaka, M., Okuda, H., Kurihara, M
  • Journal Title: J. Org. Chem Volume: 75 Pages: 5234-5239
  • Peer Reviewed
• [Journal Article] Three-Dimensional Structural Control of Diastereomeric Leu-Leu-Aib-Leu-Leu-Aib Sequences in the Solid State (2010)
  • Author(s): Demizu, Y.
  • Journal Title: J Org.Chem. Volume: 75 Pages: 5234-5239
  • Peer Reviewed
• [Journal Article] Controlling the helical screw sense of peptides with C-terminal L-valine (2010)
  • Author(s): Demizu, Y.
  • Journal Title: J.Pent. Sci. Volume: 16 Pages: 153-158
  • Peer Reviewed
• [Journal Article] Solid-state conformation of diastereomeric-Pro-Pro-(Aib)_4 sequences (2010)
  • Author(s): M.Oba
  • Journal Title: Tetrahedron Volume: 66 Pages: 2293-2296
  • Peer Reviewed
• [Journal Article] Conformational analysis of water-soluble oligopeptide composed of chiral cyclic α, α-disubstituted α-amino acids (2010)
  • Author(s): Y.Demizu
  • Journal Title: Peptide Science 2009 Pages: 381-382
• [Journal Article] Controlling the helical screw sense of peptides by N-terminal praline (2010)
  • Author(s): N.Yamagata
  • Journal Title: Peptide Science 2009 Pages: 383-384
• [Journal Article] Computational study on helical structure of Chiral α, α-Disubstituted oligopeptides (2010)
  • Author(s): M.Kurihara
  • Journal Title: Peptide Science 2009 Pages: 385-386
• [Journal Article] Sequence-specific cleavage of DNA by peptide nucleic acids conjugated with metal complexes (2010)
  • Author(s): T.Sugiyama
  • Journal Title: Peptide Science 2009 Pages: 425-426
• [Journal Article] Conformations of peptides containing a chiral cyclic α, α-disubstituted α-amino acid within the sequence of Aib residues (2010)
  • Author(s): Demizu, Y.
  • Journal Title: J.Pept.Sci. Volume: 16 Pages: 621-626
  • Peer Reviewed
• [Journal Article] Stabilized α-helix-catalyzed enantioselective epoxidation of α, β-unsaturated ketones (2010)
  • Author(s): Nagano, M
  • Journal Title: Org.Lett. Volume: 12 Pages: 3564-3566
  • Peer Reviewed
• [Journal Article] Computational study on drug design and prediction of bioactivity for regulation of non-controlled psychotropic substances (2010)
  • Author(s): M.Kurihara
  • Journal Title: Bull. Natl.Inst.Health Sci. Volume: 128 Pages: 29-33
  • NAID: 40017404207
  • Peer Reviewed
• [Presentation] ジ置換アミノ酸によるLD-ペプチドの二次構造制御 (2013)
  • Author(s): 出水庸介,土井光暢,佐藤由紀子,田中 正一,栗原正明
  • Organizer: 日本薬学会第133 年会
  • Place of Presentation: 横浜
• [Presentation] 安定化ヘリカルペプチドを用いたVDR-コアクチベータ結合阻害剤の創製 (2013)
  • Author(s): 名児耶早織,出水庸介,佐藤由紀子,正 田卓司,土井光暢,田中正一,栗原正明
  • Organizer: 日本薬学会第133 年会
  • Place of Presentation: 横浜
• [Presentation] らせん構造を有する新規フォルダマーの創製 (2013)
  • Author(s): 山崎徳和,出水庸介,正田卓司,佐藤由 紀子,栗原正明
  • Organizer: 日本薬学会第133 年会
  • Place of Presentation: 横浜
• [Presentation] LXXLL モチーフを有する安定化ヘリカルペプチド (2013)
  • Author(s): 白川真奈美,名児耶早織,出水庸介,正 田卓司,佐藤由紀子,栗原正明
  • Organizer: 日本薬学会第133 年会
  • Place of Presentation: 横浜
• [Presentation] 安定化ヘリカルペプチドを用いたVDR 転写阻害剤の設計と合成 (2012)
  • Author(s): 名児耶早織,出水庸介,佐藤由紀子,土 井光暢,田中正一,栗原正明
  • Organizer: 日本ケミカルバイオロジー学会 第7回年会
  • Place of Presentation: 京都
• [Presentation] 安定化ヘリカルペプチドを用いたビタミンD 受容体転写阻害剤の創製 (2012)
  • Author(s): 名児耶早織,出水庸介,山縣奈々子,佐 藤由紀子,土井光暢,田中正一,栗原正 明
  • Organizer: 日本薬学会第132 年会
  • Place of Presentation: 札幌
• [Presentation] 安定化ヘリカルペプチドを用いたVDR転写阻害剤の設計と合成 (2012)
  • Author(s): 名児耶早織
  • Organizer: 日本ケミカルバイオロジー学会 第７回年会
  • Place of Presentation: 京都
• [Presentation] キラルアセタールを有する６員環アミノ酸の合成とそのオリゴマーの配座解析 (2012)
  • Author(s): 石川奈保子
  • Organizer: 第38回反応と合成の進歩シンポジウム
  • Place of Presentation: 東京
• [Presentation] リジン側鎖を持ったβ キラルペプチド核酸の合成 (2012)
  • Author(s): 杉山亨
  • Organizer: 第49 回ペプチド討論会
  • Place of Presentation: 鹿児島
• [Presentation] アジド基を有するキラル五員環アミノ酸とそのペプチドの合成 (2012)
  • Author(s): 今西愛
  • Organizer: 第49 回ペプチド討論会
  • Place of Presentation: 鹿児島
• [Presentation] ペンダント型不斉中心を有する環状α,α-ジ置換アミノ酸の合成 (2012)
  • Author(s): 加藤郁美
  • Organizer: 第49 回ペプチド討論会
  • Place of Presentation: 鹿児島
• [Presentation] 安定化ヘリカルペプチドを用いたビタミンD受容体転写阻害剤の創製 (2012)
  • Author(s): 名児耶早織
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 札幌
• [Presentation] ステープルペプチドを用いたα,β-不飽和ケトンの不斉エポキシ化 (2011)
  • Author(s): 出水庸介
  • Organizer: 第55回日本薬学会関東支部大会
  • Place of Presentation: 千葉
  • Year and Date: 2011-10-08
• [Presentation] Design of Stabilized α-Helical Peptides for Transcriptional Inhibitor of Nuclear Receptor (2011)
  • Author(s): S. Nagoya, Y. Demizu, Y. Sato, M. Doi, M. Tanaka, H. Okuda, M. Kurihara
  • Organizer: AIMECS11
  • Place of Presentation: Tokyo
• [Presentation] 安定化ヘリカルペプチドを用いたα,β-不飽和ケトンの不斉エポキシ化 (2011)
  • Author(s): 出水庸介,名児耶早織,佐藤由紀子,奥 田晴宏,栗原正明,土井光暢,田中正一
  • Organizer: 第37回反応と合成の進歩シンポジウム
  • Place of Presentation: 徳島
• [Presentation] Design of a stabilized helical peptides and its application (2011)
  • Author(s): M. Kurihara, Y. Demizu, N. Yamagata, Y. Sato, Y. Takeuchi, M. Doi, M. Tanaka, H. Okuda
  • Organizer: 22nd American peptide symposium
  • Place of Presentation: San Diego
• [Presentation] ヘリカルペプチドの制御とカルコン類の不斉エポキシ化への応用 (2011)
  • Author(s): 出水庸介,山縣奈々子,佐藤由紀子,土 井光暢,田中正一,奥田 晴宏,栗原 正 明
  • Organizer: 日本薬学会第131 年会
  • Place of Presentation: 静岡
• [Presentation] ノンセコ型VDRリガンドの創製およびVDRとの相互作用解析 (2011)
  • Author(s): 出水庸介
  • Organizer: 日本ケミカルバイオロジー学会第6回年会
  • Place of Presentation: 東京
• [Presentation] Design of a stabilized helical peptides and its application (2011)
  • Author(s): M.Kurihara
  • Organizer: 22^<nd> American peptide symposium
  • Place of Presentation: San Diego
• [Presentation] Controlling helical peptides containing equal numbers of L- and D-amino acids (2011)
  • Author(s): Y.Demizu
  • Organizer: 22^<nd> American peptide symposium
  • Place of Presentation: San Diego
• [Presentation] Helical secondary structures of oligopeptides composed of chiral five-membered ring amino acids (2011)
  • Author(s): M.Tanaka
  • Organizer: 22^<nd> American peptide symposium
  • Place of Presentation: San Diego
• [Presentation] Design of non-secosteroidal VDR ligands and binding mode to VDR-LBD (2011)
  • Author(s): Y.Demizu
  • Organizer: 4^<th> European Conference on Chemisitry for Life Sciences
  • Place of Presentation: Budapest, Hungary
• [Presentation] Design of Stapled Helical Peptides for Catalyic Eenantioselective Epoxidation of α,α-Unsaturated Ketones (2011)
  • Author(s): 出水庸介
  • Organizer: 第48回ペプチド討論会
  • Place of Presentation: 札幌
• [Presentation] Design of Stable Helical Peptides (2011)
  • Author(s): 栗原正明
  • Organizer: 第48回ペプチド討論会
  • Place of Presentation: 札幌
• [Presentation] キラルな5員環状アミノ酸からなるペプチドの合成とコンフォメーション解析 (2011)
  • Author(s): 平田陽子
  • Organizer: 第48回ペプチド討論会
  • Place of Presentation: 札幌
• [Presentation] 配座自由度を制限したエンドモルフィン-2誘導体の設計・合成 (2011)
  • Author(s): 花田智美
  • Organizer: 第48回ペプチド討論会
  • Place of Presentation: 札幌
• [Presentation] Design of Non-secosteroidal VDR Ligands and Hydrogen-Bond Network in VDR-LBD (2011)
  • Author(s): M.Kurihara
  • Organizer: AIMECS11
  • Place of Presentation: Tokyo
• [Presentation] Synthesis of Cyclic Amino Acids with Two Chiral Centers and Secondary Structures of Their Peptides (2011)
  • Author(s): M.Oba
  • Organizer: AIMECS11
  • Place of Presentation: Tokyo
• [Presentation] タンパク質間相互作用を制御する安定化ヘリカルペプチドの創製 (2010)
  • Author(s): 山縣奈々子
  • Organizer: 第54回日本薬学会関東支部大会
  • Place of Presentation: 東京
  • Year and Date: 2010-10-02
• [Presentation] ハイブリッドペプチドフォールダマーの設計と合成 (2010)
  • Author(s): 山縣奈々子
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
• [Presentation] 光学活性6員環状ジ置換アミノ酸の合成とそのペプチドの2次構造研究 (2010)
  • Author(s): 平田貴之
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
• [Presentation] 2つのアセタールを有する6員環状アミノ酸の合成とそのオリゴマーの2次構造解析 (2010)
  • Author(s): 加藤和也
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
• [Presentation] C末端バリンによるヘリカル二次構造の制御 (2010)
  • Author(s): 出水庸介
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
• [Presentation] シート構造を形成するペプチドの設計と合成 (2010)
  • Author(s): 筒井康平
  • Organizer: 日本薬学会130年会
  • Place of Presentation: 岡山
• [Presentation] α, α-ジ置換アミノ酸オリゴペプチドのコンフォメーション予測と解析 (2010)
  • Author(s): 栗原正明
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
• [Presentation] 光学活性5員環アミノ酸の設計合成とそのペプチドの二次構造解析 (2010)
  • Author(s): 平田陽子
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
• [Presentation] ペプチド核酸-金属錯体コンジュゲートによるDNA切断 (2010)
  • Author(s): 杉山亨
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
• [Presentation] Computational study on helical structure of α, α-disubstituted oligopeptides containing chiral α-amino acids (2010)
  • Author(s): M.Kurihara
  • Organizer: 31'st European Peptide Symposium
  • Place of Presentation: Copenhagen
• [Presentation] Structural control of diastereomeric Leu-Leu-Aib-Leu-Leu-Aib sequences (2010)
  • Author(s): Y.Demizu
  • Organizer: 31'st European Peptide Symposium
  • Place of Presentation: Copenhagen
• [Presentation] Cyclic amino acid-containing alpha-helical peptide-catalyzed enantioselective epoxidation reaction (2010)
  • Author(s): M.Tanaka
  • Organizer: 31'st European Peptide Symposium
  • Place of Presentation: Copenhagen
• [Presentation] ヘリカルペプチドの制御と核内受容体転写阻害物質への応用 (2010)
  • Author(s): 山縣奈々子
  • Organizer: 反応と合成の進歩シンポジウム
  • Place of Presentation: 名古屋
• [Presentation] Synthesis of 4-Substituted Chiral PNA Monomers (2010)
  • Author(s): T.Sugiyama
  • Organizer: 5th International Peptide Symposium
  • Place of Presentation: Kyoto
• [Presentation] Conformational studies of diastereomeric-Leu-Aib-peptides (2010)
  • Author(s): Y.Demizu
  • Organizer: 5th International Peptide Symposium
  • Place of Presentation: Kyoto
• [Presentation] Design of short α-helical peptides for transcriptional inhibitor of nuclear receptor (2010)
  • Author(s): N.Yamagata
  • Organizer: 5th International Peptide Symposium
  • Place of Presentation: Kyoto
• [Presentation] Stabilized α-helical peptide-catalyzed asymmetric epoxidation of chalcone derivatives (2010)
  • Author(s): Tanaka, M
  • Organizer: 5th International Peptide Symposium
  • Place of Presentation: Kyoto
• [Presentation] Computational study on conformation of oligopeptides containing α, α-Disubstituted Amino Acids (2010)
  • Author(s): M.Kurihara
  • Organizer: 5th International Peptide Symposium
  • Place of Presentation: Kyoto
• [Presentation] 細胞膜透過性蛍光NTAの創製
  • Author(s): 正田卓司
  • Organizer: 第56回日本薬学会関東支部大会
  • Place of Presentation: 東京