Screening of the voltage-gated sodium channel blockers to discover the lead compounds for therapeutic purposes
| Project/Area Number |
17H02199
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biomolecular chemistry
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| Research Institution | Tohoku University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
日高 將文 東北大学, 農学研究科, 助教 (00584848)
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| Project Period (FY) |
2017-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥13,910,000 (Direct Cost: ¥10,700,000、Indirect Cost: ¥3,210,000)
Fiscal Year 2020: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2019: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2017: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
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| Keywords | 電位依存性ナトリウムチャネル / 電気生理実験 / テトロドトキシン / サキシトキシンン / クロイソカイメン / サブタイプ選択性 / スクリーニング / 医薬資源 / 阻害剤探索 / 構造決定 / 神経障害性疼痛 / サキシトキシン / 医薬資源探索 / ハイスループットスクリーニング / テトロドトトキシン / 慢性疼痛 / 電気生理 / 新規医薬資源 / パッチクランプ記録法 |
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| Outline of Final Research Achievements |
We examined the sensitivity of Nav1.1-1.7 to TTX analogues provided by a collaborator and found that 1) chiriquitoxin (CHTX) exhibits low affinity to Nav1.7 due to steric repulsion against isoleucine residues in the TTX binding site, 2) contrary to previous reports, 4,9-anhydroTTX exhibits low affinity to Nav1.6, 3) the deoxy analogues exhibit low affinity to any Nav subtype.
We investigated the Nav inhibitory activity of various natural and non-natural TTX and STX derivatives provided by other collaborators and found that the one of the derivatives showed high affinity for Nav1.5, which is normally insensitive to TTX or STX.
We found arachidonic acid as an inhibitor of Nav expressed in mouse neuroblastoma Neuro 2A from the marine sponge Halichondria okadai, and investigated the details of the inhibition mechanism.
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| Academic Significance and Societal Importance of the Research Achievements |
９つある電位依存性ナトリウムチャネル(Nav)は「不整脈」や「癲癇」「慢性疼痛」の源である。こうした疾患治療の原石と言えるNav阻害剤を探索した本研究の意義は重要である。簡便かつ安価に判別できるハイスループットスクリーニング系の構築は困難であったが、代替法として多検体処理には不向きであった電気生理的手法を用いてクロイソカイメンからアラキドン酸をスクリーニングした成果を特記したい。さらに同手法を用いて特定のサブタイプに親和性または阻害性を示したテトロドトキシンおよびサキシトキシン の誘導体は医薬資源の原石であり、今後、さらに発展させていく所存である。
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Report
(5 results)
Research Products
(65 results)
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[Journal Article] Synthesis of C12-keto saxitoxin derivatives with unusual inhibitory activity against voltage‐gated sodium channels.2020
Author(s)
Adachi, K., Yamada, T., Ishizuka, H., Oki, M., Tsunogae, S., Shimada, N., Chiba, O., Orihara, T., Hidaka, M., Hirokawa, T., Odagi, M., Konoki, K., Yotsu-Yamashita, M., Nagasawa, K.
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Journal Title
Chem. Eur. J.
Volume: 26
Issue: 9
Pages: 2025-2033
DOI
Related Report
Peer Reviewed
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[Journal Article] Metabolomic study of saxitoxin analogues and biosynthetic intermediates in dinoflagellates using 15N-labelled sodium nitrate as a nitrogen source2019
Author(s)
1.Cho, Y., Tsuchiya, S., Omura, T., Koike, K., Oikawa, H., Konoki, K., Oshima, Y., Yotsu-Yamashita, M.
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Journal Title
Sci. Rep.
Volume: 9
Issue: 1
Pages: 3460-3460
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Pufferfish Saxitoxin and Tetrodotoxin Binding Protein (PSTBP) Analogues in the Blood Plasma of the Pufferfish Arothron nigropunctatus, A. hispidus, A. manilensis, and Chelonodon patoca2018
Author(s)
2.Yotsu-Yamashita, M., Nagaoka, Y., Muramoto, K., Cho, Y., Konoki, K.
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Journal Title
Mar. Drugs
Volume: 16
Issue: 7
Pages: 224-224
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] マイトトキシンの標的分子探索2021
Author(s)
此木敬一, 松本 健, 木下祥尚, 角替俊輔, 後藤萌香, 吉尾柊太郎, 田端滉樹, 長 由扶子, 八代田陽子, Katherine Chan, Amy Hin Yan Tong, Kamaldeep Kaur Aulakh, Andrea Habsid, 山下まり, 松森信明, Jason Moffat, Charles Boone, 吉田 稔, 村田道雄
Organizer
新学術領域研究（研究領域提案型）「化学コミュニケーションのフロンティア」第8回公開シンポジウム
Related Report
Invited
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[Presentation] Metabolomic study of saxitoxin biosynthesis in dinoflagellates using 15N-labelled sodium nitrate as a nitrogen source2019
Author(s)
〇Cho, Y., Tsuchiya, S., Omura, T., Koike, K., Oikawa, H., Konoki, K., Oshima, Y. and Yotsu-Yamashita, M.
Organizer
Gordon Research Conference, Mycotoxins and Phycotoxins (Stonehill College, Easton, USA, June 16 - 21, 2019)
Related Report
Int'l Joint Research
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[Presentation] Screening of novel secondary metabolites from microorganisms associated with the marine sponge Halichondria okadai2019
Author(s)
〇Goto, M., Kikuchi, S., Okada, K., Cho, Y., Yotsu-Yamashita, M. and Konoki, K.
Organizer
Tohoku University’s Chemistry Summer School (Tohoku University, Sendai, Aug 27-28)
Related Report
Int'l Joint Research
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[Presentation] Isolation and structural elucidation of tetrodotoxin related compounds from pufferfish2019
Author(s)
〇Yaegashi, Y., Ueyama, N., Kudo, Y., Cho, Y., Konoki, K. and Yotsu-Yamashita, M.
Organizer
Tohoku University’s Chemistry Summer School (Tohoku University, Sendai, Aug 27-28)
Related Report
Int'l Joint Research
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[Presentation] Sensitivity of the voltage-gated sodium channel subtypes, Nav1.1 to Nav1.7, against guanidine-containing natural products and their analogues2019
Author(s)
Tadaaki Tsukamoto, Yukie Chiba, Shunsuke Tsunogae, Tomoshi Yamada, Yuko Cho, Ryo Sakakibara, Takuya Imazu, Shouta Tokoro, Yoshiki Satake, Yuki Ishikawa, Yoshiki Nakane, Masaatsu Adachi, Atsuo Nakazaki, Toshio Nishikawa, Minoru Wakamori, Mari Yotsu-Yamashita, Keiichi Konoki
Organizer
新学術領域研究(研究領域提案型)「化学コミュニケーションのフロンティア」第1回国際シンポジウム（ISCC2019）（第4回公開シンポジウム）
Related Report
Int'l Joint Research
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[Presentation] テトロドトキシン類縁体に対する電位依存性ナトリウムチャネルの感受性評価2018
Author(s)
塚本匡顕, 千葉雪絵, 若森 実, 日高將文, 山田智士, 角替俊輔, 長 由扶子, 榊原 良, 今津拓也, 所 聖太, 佐竹佳樹, 安立昌篤, 西川俊夫, 山下まり, 此木敬一
Organizer
第60回天然有機化合物討論会
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