Structural analysis of IL-18 inhibitor to enhance the activity

• Project/Area Number: 19K08249
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• 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): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: IL-18 / 阻害薬剤 / ペプチド / 立体構造解析 / 立体構造 / 創薬 / IL18 / inhibitor / 3D structure

Outline of Research at the Start

本研究期間においては、新規に発見したIL-18シグナルペプチド由来分子標的阻害剤を基盤とした薬効増強等を目的とした立体構造・機能相関解析を行う。すでに、IL-18リガンドのmature formへの変換の際に切り出されるシグナルペプチドの阻害効果を発見し、その立体構造的特徴と結合様式の解明・GVHDモデルマウス生体内における薬効解析等について終了している。さらなる結合増強・安定化などによる薬効を増強するために、すでに得られた原子解像度の立体構造情報をもとに構造改変・立体構造スクリーニング(改変ペプチド、構造類似合成ポリマー、低分子薬剤等)による新規分子開発を進める。

Outline of Final Research Achievements

We studied the derivative peptide molecules designed by using the original peptide, which can inhibit IL-18 function. The design of the derivatives was done by using information about the intermoelcular interactions between the peptides and IL-18 ligand molecule. Finally, we could establish the system that can search possible stable strutures in the water.

Academic Significance and Societal Importance of the Research Achievements

この安定構造をもとに各種変異体設計を行うことが可能となった。それを用いたin vivoでの効果発現研究を進めることができる基盤を確立したことで、in silicoタンパク複合体構造解析設計システム等を有機的に複合することにより、新規に発見されたペプチド分子の薬効増強など応用開発が可能と考えられ、今後の難治性疾患の治療に寄与できる可能性がある。

Research Products

• [Journal Article] Novel nonsense mutation in the SLC39A4 gene in a Japanese boy with mild acrodermatitis enteropathica. (2021)
  • Author(s): Ichiki N, Tawada C,Kato Z, Nakano H, Seishima M.J
  • Journal Title: Dermatol. Volume: 48
  • Peer Reviewed / Open Access
• [Journal Article] Clinical and Immunological Heterogeneity in Japanese Patients with Gain-of-Function Variants in STAT3. (2021)
  • Author(s): Tanita K, Sakura F, Nambu R, Tsumura M, Imanaka Y, Ohnishi H, Kato Z, Pan J, Hoshino A, Suzuki K, Yasutomi M, Umetsu S, Okada C, Takagi M, Imai K, Ohara O, Muise AM, Okada S, Morio T, Kanegane H.
  • Journal Title: J Clin Immunol. Volume: 41 Pages: 780-790
  • Peer Reviewed / Open Access
• [Journal Article] Novel Homozygous Mutation Destabilizes IKKβ and Leads to Human Combined Immunodeficiency. (2021)
  • Author(s): Qin T, Jia Y, Liu Y, Dai R, Zhou L, Okada S, Tsumura M, Ohnishi H, Kato Z, Kanegane H, Sun X, Zhao X.A
  • Journal Title: Front Immunol. Volume: 11 Pages: 517-544
  • Peer Reviewed / Open Access
• [Journal Article] IRAK4 Deficiency Presenting with Anti-NMDAR Encephalitis and HHV6 Reactivation. (2021)
  • Author(s): Nishimura S, Kobayashi Y, Ohnishi H, Moriya K, Tsumura M, Sakata S, Mizoguchi Y, Takada H, Kato Z, Sancho-Shimizu V, Picard C, Irani SR, Ohara O, Casanova JL, Puel A, Ishikawa N, Okada S, Kobayashi M.
  • Journal Title: J Clin Immunol. Volume: 41 Pages: 125-135
  • Peer Reviewed / Open Access
• [Journal Article] A Novel Homozygous Mutation Destabilizes IKKβ and Leads to Human Combined Immunodeficiency (2021)
  • Author(s): Qin Tao、Jia Yanjun、Liu Yuhang、Dai Rongxin、Zhou Lina、Okada Satoshi、Tsumura Miyuki、Ohnishi Hidenori、Kato Zenichiro、Kanegane Hirokazu、Sun Xiulian、Zhao Xiaodong
  • Journal Title: Frontiers in Immunology Volume: 11 Pages: 517544-517544
  • DOI: 10.3389/fimmu.2020.517544
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Oral immunotherapy with antigenicity-modified casein induces desensitization in cow's milk allergy. (2020)
  • Author(s): Kawamoto N., Kaneko H., Kawamoto M., Ohnishi H., Matsui E., Teramoto T., Kato Z., Fukao T., Ueno H. M., Nakano T., Kondo N
  • Journal Title: Allergy Volume: 75 Issue: 1 Pages: 197-200
  • DOI: 10.1111/all.13965
  • Peer Reviewed / Open Access
• [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 Issue: 1 Pages: 6160-6160
  • DOI: 10.1038/s41598-019-42661-5
  • NAID: 120007006235
  • Peer Reviewed / Open Access
• [Journal Article] Prominent Dermal Langerhans Cells in an Omenn Syndrome Patient With a Novel Mutation in the IL2RG Gene (2019)
  • Author(s): Ibusuki Atsuko、Nishikawa Takuro、Hiraki Tsubasa、Okano Tsubasa、Imai Kohsuke、Kanegane Hirokazu、Ohnishi Hidenori、Kato Zenichiro、Fujii Kazuyasu、Tanimoto Akihide、Kawano Yoshifumi、Kanekura Takuro
  • Journal Title: The Journal of Dermatology Volume: 46 Issue: 11 Pages: 1019-1023
  • DOI: 10.1111/1346-8138.15054
  • Peer Reviewed / Open Access