Establishment of a method of IL-18 inhibitor based on a new molecular mechanism

• Project/Area Number: 16K10025
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Gifu University
• Principal Investigator: Kato Zenichiro 岐阜大学, 大学院医学系研究科, 教授 (90303502)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: IL-18 / 阻害薬 / 阻害剤 / 立体構造

Outline of Final Research Achievements

We performed analyses of the molecular mechanism by IL-18 inhibitor. In addition to the cutokine inhibition experiments, the molecular interaction analysis was done in atomic resolution. Especially, the atomic interactions between IL-18 ligand and the innate inihibitory peptide were precisely determined by using nuclear magnetic resonance technique. Using the above biological and molecular information, further improvement of the inhibitor should be feasible.

Academic Significance and Societal Importance of the Research Achievements

病気に関与する分子をそれぞれ単にひとつの点として考えるのではなく、ナノメーター以下の原子レベルでの分子構造をもとに病態解析及びその治療法の開発を行うものであり、詳細な構造を決定したことにより、単なるランダムスクリーニングではなく、立体構造に基づいた論理的な蛋白工学的機能分子デザイン・開発が可能となった。本研究にて開発される治療分子を得ることは、免疫システムのkey modulatorを自在に調節可能となる事に繋がり、アレルギーのみならず、リウマチ性疾患や多発性硬化症などの神経難病を含む自己免疫異常に対しても有効な手段の一つとなり、対象となるポピュレーションは大きい。

Research Products

• [Journal Article] An innate interaction between IL-18 and the propeptide that inactivates its precursor form (2019)
  • Author(s): Naotaka Tsutsumi, Ayumi Yokota, Takeshi Kimura, Zenichiro Kato, Toshiyuki Fukao, Masahiro Shirakawa, Hidenori Ohnishi & Hidehito Tochio
  • Journal Title: Scientific Reportsvolume Volume: 9 Pages: 6160
  • DOI: https://doi.org/10.1038/s41598-019-42661-5
  • Peer Reviewed / Open Access
• [Journal Article] Alanine-scanning mutagenesis of human signal transducer and activator of transcription 1 to estimate loss- or gain-of-function variants. (2017)
  • Author(s): Kagawa R, Fujiki R, Tsumura M, Sakata S, Nishimura S, Itan Y, Kong XF, Kato Z, Ohnishi H, Hirata O, Saito S, Ikeda M, El Baghdadi J, Bousfiha A, Fujiwara K, Oleastro M, Yancoski J, Perez L, Danielian S, Ailal F, Takada H, Hara T, Puel A, Boisson-Dupuis S, Bustamante J, Casanova JL, Ohara O, Okada S, Kobayashi M.
  • Journal Title: J Allergy Clin Immunol. Volume: 140 Pages: 232-241
  • DOI: doi: 10.1016/j.jaci.2016.09.035.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Outbreak of immediate-type hydrolyzed wheat protein allergy due to a facial soap in Japan. (2017)
  • Author(s): Yagami A, Aihara M, Ikezawa Z, Hide M, Kishikawa R, Morita E, Chinuki Y, Fukutomi Y, Urisu A, Fukushima A, Itagaki Y, Sugiura SI, Tanaka H, Teshima R, Kato Z, Noguchi E, Nakamura M, Saito H, Matsunaga K.
  • Journal Title: J Allergy Clin Immunol. Volume: 140 Pages: 879-881
  • DOI: doi: 10.1016/j.jaci.2017.03.019.
  • Peer Reviewed / Open Access