Approach to drug discovery of microbial inhibitors of lipid metabolism

• Project/Area Number: 16K18900
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Natural medicines
• Research Institution: Kitasato University
• Principal Investigator: Ohshiro Taichi 北里大学, 薬学部, 講師 (30458765)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 天然物 / 脂質代謝 / 動脈硬化 / 脂肪肝 / ケミカルバイオロジー / 阻害剤 / 薬学 / 脂質異常症 / 微生物

Outline of Final Research Achievements

In this study, 1) screening for microbial inhibitors of lipid metabolism (neutral lipids; cholesteryl ester (CE) and triglyceride (TG)), 2) in vivo test of pyripyropene A derivative, highly SOAT2 selective inhibitor, using a mouse model of fatty liver diseases (NAFLD/NASH) and 3) search for the mode of action of new microbial inhibitors of lipid metabolism (from 1)) and beauveriolide III, SOAT1-selective inhibitor in intact cells, using biochemistry techniques were investigated.

Research Products

• [Journal Article] Design and Synthesis of A-Ring Simplified Pyripyropene A Analogues as Potent and Selective Synthetic SOAT2 Inhibitors (2018)
  • Author(s): Ohtawa Masaki、Arima Shiho、Ichida Naoki、Terayama Tomiaki、Ohno Hironao、Yamazaki Takaya、Ohshiro Taichi、Sato Noriko、Omura Satoshi、Tomoda Hiroshi、Nagamitsu Tohru
  • Journal Title: ChemMedChem Volume: 13 Issue: 5 Pages: 411-421
  • DOI: 10.1002/cmdc.201700645
  • Peer Reviewed
• [Journal Article] Discovery of a Fungal Multicopper Oxidase That Catalyzes the Regioselective Coupling of a Tricyclic Naphthopyranone To Produce Atropisomers (2018)
  • Author(s): Mio Kawaguchi, Taichi Ohshiro, Masayuki Toyoda, Satoshi Ohte, Junji Inokoshi, Isao Fujii, Hiroshi Tomoda
  • Journal Title: Angwandte Chemie Int. Edt. Volume: 57 Issue: 18 Pages: 5115-5119
  • DOI: 10.1002/anie.201800415
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Callyspongiamides A and B, sterol O-acyltransferase inhibitors, from the Indonesian marine sponge Callyspongia sp. (2018)
  • Author(s): Kapojos MM, Abdjul DB, Yamazaki H, Ohshiro T, Rotinsulu H, Wewengkang DS, Sumilat DA, Tomoda H, Namikoshi M, Uchida R.
  • Journal Title: Bioorg Med Chem Lett. Volume: 28 Issue: 10 Pages: 1911-1914
  • DOI: 10.1016/j.bmcl.2018.03.077
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Selective inhibition of sterolO-acyltransferase 1 isozyme by beauveriolide III in intact cells (2017)
  • Author(s): T. Ohshiro, K. Kobayashi, M. Ohba, D. Matsuda, L. L. Rudel, T. Takahashi, T. Doi, H. Tomoda
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 4163-4163
  • DOI: 10.1038/s41598-017-04177-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pseudopyronine B, an inhibitor of sterol O-acyltransferase, produced by Pseudomonas sp. BYK11209. (2017)
  • Author(s): Suzuki A, Fukuda T, Kobayashi K, Ohshiro T, Tomoda H.
  • Journal Title: J Antibiot, Volume: 70 Issue: 1 Pages: 798-805
  • DOI: 10.1038/ja.2016.46
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Biseokeaniamides A, B, and C, Sterol O-Acyltransferase Inhibitors from an Okeania sp. Marine Cyanobacterium. (2017)
  • Author(s): Iwasaki A, Tadenuma T, Sumimoto S, Ohshiro T, Ozaki K, Kobayashi K, Teruya T, Tomoda H, Suenaga K.
  • Journal Title: J Nat Prod. Volume: 80 Issue: 4 Pages: 1161-1166
  • DOI: 10.1021/acs.jnatprod.7b00137
  • Peer Reviewed
• [Journal Article] 7-Chlorofolipastatin, an inhibitor of sterol O-acyltransferase, produced by marine-derived Aspergillus ungui NKH-007. (2016)
  • Author(s): Uchida R, Nakajyo K, Kobayashi K, Ohshiro T, Terahara T, Imada C, Tomoda H.
  • Journal Title: J Antibiot Volume: 69 Issue: 8 Pages: 647-651
  • DOI: 10.1038/ja.2016.27
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Design, Synthesis, and Biological Evaluation of Beauveriolide Analogues Bearing Photoreactive Amino Acids (2016)
  • Author(s): Masuda Y, Aoyama K, Yoshida M, Kobayashi K, Ohshiro T, Tomoda H, Doi T.
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 64 Issue: 7 Pages: 754-765
  • DOI: 10.1248/cpb.c16-00095
  • NAID: 130005160040
  • ISSN: 0009-2363, 1347-5223
  • Peer Reviewed / Open Access
• [Journal Article] Discovery of SOAT2 Inhibitors from Synthetic Small Molecules (2016)
  • Author(s): Kobayashi, K.; Ohshiro, T.; Tomoda, H.; Yin, F.; Cui, H.-L.; Chouthaiwale, P. V.; Tanaka, F.
  • Journal Title: Bioorg. Med. Chem Lett. Volume: 26 Issue: 24 Pages: 5899-5901
  • DOI: 10.1016/j.bmcl.2016.11.008
  • Peer Reviewed
• [Presentation] ピリピロペン誘導体の抗動脈硬化作用 (II) (2018)
  • Author(s): 大城太一、大多和正樹、長光 亨、Rudel Lawrence、供田 洋
  • Organizer: 日本薬学会第138年会
• [Presentation] 真菌由来の新規 SOAT 阻害剤 celludinone A の立体化学に関する研究 (2018)
  • Author(s): 関 怜子、大城太一、供田 洋
  • Organizer: 日本薬学会第138年会
• [Presentation] ボーベリオライド誘導体の抗動脈硬化作用 (2017)
  • Author(s): 大城太一、伊牟田聡、土黒一郎、高橋孝志、土井隆行、石橋俊、供田洋
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台市
  • Year and Date: 2017-03-24
• [Presentation] 位置選択的モナピノン二量体化酵素 MCE の基質特異性に関する研究 (2017)
  • Author(s): 大城太一、豊田雅幸 、 川口未央 、 供田 洋
  • Organizer: 平成29年度生命科学系合同年次大会
• [Presentation] SOAT2 選択的阻害剤は脂肪性肝疾患に有効か? (2017)
  • Author(s): 大城太一、大多和正樹 、長光 亨 、Rudel Lawrence、石橋 俊、供田 洋
  • Organizer: 第59回 日本脂質生化学会
• [Presentation] Taichi Ohshiro, Masaki Ohtawa, Tohru Nagamitsu, Hiroaki Yagyu, Lawrence L. Rudel, Shun Ishibashi, Hiroshi Tomoda (2017)
  • Author(s): PRD125, a highly potent SOAT2 inhibitor, attenuates both atherosclerosis and fatty liver progression in cholesterol diet-fed rabbits.
  • Organizer: AHA Scientific Sessions 2017
  • Int'l Joint Research
• [Presentation] SOAT2選択的阻害剤ピリピロペン誘導体の抗動脈硬化作用 (2016)
  • Author(s): 大城太一、大多和正樹、長光 亨、Lawrence L. Rudel、供田 洋
  • Organizer: 第58回日本脂質生化学会
  • Place of Presentation: 秋田市
  • Year and Date: 2016-06-09
• [Remarks] 北里大学薬学部微生物薬品製造学教室
  • URL: http://www.pharm.kitasato-u.ac.jp/microbchem/wei_sheng_wu_yao_pin_zhi_zao_xue/Welcome.html
• [Patent(Industrial Property Rights)] ステロールO-アシルトランスフェラーゼ2(SOAT2)阻害活性を有する新規化合物及びその製造方法 (2017)
  • Inventor(s): 供田洋、福田隆志、大城太一
  • Industrial Property Rights Holder: 北里大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-005260
  • Filing Date: 2017-01-16