Chemical Hybridization of Vizantin and Lipid A to Generate a Novel LPS Antagonist

• Yamamoto Hirofumi

  Faculty of Pharmaceutical Sciences, Tokushima Bunri University

• Oda Masataka

  Faculty of Pharmaceutical Sciences, Tokushima Bunri University Division of Microbiology and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences

• Kanno Marina

  Faculty of Pharmaceutical Sciences, Tokushima Bunri University

• Tamashiro Shota

  Faculty of Pharmaceutical Sciences, Tokushima Bunri University

• Tamura Ikuko

  Faculty of Pharmaceutical Sciences, Tokushima Bunri University

• Yoneda Toshihiko

  Faculty of Pharmaceutical Sciences, Tokushima Bunri University

• Yamasaki Naoto

  Faculty of Pharmaceutical Sciences, Tokushima Bunri University

• Domon Hisanori

  Division of Microbiology and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences

• Nakano Mayo

  Faculty of Pharmaceutical Sciences, Tokushima Bunri University

• Takahashi Hironobu

  Faculty of Pharmaceutical Sciences, Tokushima Bunri University

• Terao Yutaka

  Division of Microbiology and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences

• Kasai Yusuke

  Faculty of Pharmaceutical Sciences, Tokushima Bunri University

• Imagawa Hiroshi

  Faculty of Pharmaceutical Sciences, Tokushima Bunri University

抄録

Lipopolysaccharide (LPS) antagonists have attracted considerable interest as promising candidates for the treatment of severe sepsis triggered by Gram-negative bacteria. In this article, we describe the development of a novel LPS antagonist based on chemical hybridization of vizantin and the hydrophobic molecular unit of LPS (lipid A). Vizantin, 6,6′-bis-O-(3-nonyldodecanoyl)-α,α′-trehalose, was designed as an immunostimulator from a structure–activity relationship (SAR) study with trehalose 6,6′-dicorynomycolate (TDCM). Our recent study indicated that vizantin displays adjuvant activity by specifically binding to the Toll-like receptor 4 (TLR4)/MD2 protein complex. Because lipid A unit (or LPS) is also known to trigger an inflammatory response via the same TLR4/MD2 complex as vizantin, we designed a hybrid compound of vizantin and lipid A with the aim of developing a novel biofunctional glycolipid. Focusing on the antagonism to Escherichia coli LPS in an in vitro model with human macrophages (THP-1 cells), we identified a potent LPS antagonist among the synthesized hybrid compounds. The novel LPS antagonist effectively inhibited LPS-induced release of tumor necrosis factor-alpha (TNF-α) in a dose-dependent manner with an IC₅₀ value of 3.8 nM, making it a candidate for the treatment drug of Gram-negative sepsis and/or septic shock.

収録刊行物

• ＣＨＥＭＩＣＡＬ　＆　ＰＨＡＲＭＡＣＥＵＴＩＣＡＬ　ＢＵＬＬＥＴＩＮ

  ＣＨＥＭＩＣＡＬ　＆　ＰＨＡＲＭＡＣＥＵＴＩＣＡＬ　ＢＵＬＬＥＴＩＮ 64 (3), 246-257, 2016

  公益社団法人 日本薬学会

キーワード

• vizantin
• lipopolysaccharide (LPS)
• lipid A
• endotoxin
• antagonist
• Toll-like receptor 4 (TLR4)

詳細情報

• CRID: 1390282679154276736
• NII論文ID: 130005131585
• NII書誌ID: AA00602100
• DOI: 10.1248/cpb.c15-00828
• ISSN: 13475223
• ISSN: 00092363
• NDL書誌ID: 027133481
• PubMed: 26725501
• Web Site: http://id.ndl.go.jp/bib/027133481
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I027133481
• Web Site: https://www.jstage.jst.go.jp/article/cpb/64/3/64_c15-00828/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2016310935
• 本文言語コード: en
• データソース種別:
  • JaLC
  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
  • KAKEN
• 抄録ライセンスフラグ: 使用不可