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Structural studies of HLA to develop of rational medicines for DIHS treatment

Research Project

Project/Area Number 21K08358
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53050:Dermatology-related
Research InstitutionTeikyo University

Principal Investigator

Kusakabe Yoshio  帝京大学, 薬学部, 講師 (30338537)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsアレルギー / 重症型薬疹 / DIHS / 立体構造 / インシリコ / 重症薬疹 / HLA / 薬疹 / 構造解析
Outline of Research at the Start

本研究では、HLA-B*13:01単独およびHLA-B*13:01-アロプリノール複合体、HLA-B*13:01-フェノバルビタール複合体の立体構造をX線結晶解析の手法を用いて明らかにし、HLA-B*13:01単独に比べHLA-B*13:01-アロプリノール複合体、HLA-B*13:01-フェノバルビタール複合体に高い親和性を持つペプチドをin silico分子ドッキングの手法を用いて同定することで、HLA-B*13:01を持っている人がDIHSを発症しない新規ペプチド様アレルギー薬開発の手がかりを得ることを目指す。

Outline of Final Research Achievements

In this study, we aimed to clarify the three-dimensional structure of HLA-B*13:01 by X-ray crystal structure analysis. Since HLA-B*13:01 forms a complex with β2-Microglobulin, it is necessary to obtain a complex of the two in order to perform crystal structure analysis. For each protein, expression systems with and without His tags were constructed, and expression and purification were performed, and we succeeded in obtaining proteins free of impurities. After that, we confirmed the formation of the complex by gel filtration chromatography, but we were unable to obtain a complex with or without a tag. Therefore, we predicted the complex between HLA-B*13:01 and β2-Microglobulin in silico, and found that a peptide of dipeptide or more is required for the complex to form.

Academic Significance and Societal Importance of the Research Achievements

HLA-B*13:01のX線結晶構造解析を目指したが、β2-Microgloblinとの複合体を得ることが出来なかった。そこで、HLA-B*13:01とβ2-Microgloblinの複合体をin silicoで明らかにし、DIHSを引き起こすアロプリノールとフェノバルビタールをドッキングの手法で結合様式を予測した結果、共通の結合が見つけることが出来た。このことからHLA-B*13:01を持つ人に対して薬疹を引き起こす医薬品の共通構造を予測することが出来、この結果を応用することでHLA-B*13:01を持つ人が薬疹を引き起こす医薬品をあらかじめ予測することが出来ると考えられる。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (3 results)

All 2023

All Journal Article (1 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (2 results) (of which Int'l Joint Research: 2 results)

  • [Journal Article] Isolation and identification of the new baicalin target protein to develop flavonoid structure-based therapeutic agents2023

    • Author(s)
      Kusakabe Yoshio、Moriya Shun-Suke、Sugiyama Toru、Miyata Yoshiki
    • Journal Title

      Bioorganic & Medicinal Chemistry

      Volume: 90 Pages: 117362-117362

    • DOI

      10.1016/j.bmc.2023.117362

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] The effect of Baicalin on Annexin A1 in Stevens-Johnson syndrome/toxic epidermal necrolysis2023

    • Author(s)
      Yoshio Kusakabe
    • Organizer
      11th International Congress of Cutaneous Adverse Drug Reactions (iSCAR) 2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Drug eruption caused by anti-androgen drugs and reports of Stevens Johnson syndrome/toxic epidermal necrolysis in Japan.2023

    • Author(s)
      Kae Kobayashi, Mikiko Tohyama, Chisato Sunaga, Hiroomi Hosaka, Yoshio Kusakabe, Hideaki Watanabe
    • Organizer
      25th World congress of Dermatology, Singapore, 2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research

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Published: 2021-04-28   Modified: 2025-01-30  

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