title: Chemical Hybridization of Vizantin and Lipid A to Generate a Novel LPS Antagonist.
abstract: 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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokushima Bunri University.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Masataka
authors.initials: M
authors.lastname: Oda
authors.forename: Marina
authors.initials: M
authors.lastname: Kanno
authors.forename: Shota
authors.initials: S
authors.lastname: Tamashiro
authors.forename: Ikuko
authors.initials: I
authors.lastname: Tamura
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yoneda
authors.forename: Naoto
authors.initials: N
authors.lastname: Yamasaki
authors.forename: Hisanori
authors.initials: H
authors.lastname: Domon
authors.forename: Mayo
authors.initials: M
authors.lastname: Nakano
authors.forename: Hironobu
authors.initials: H
authors.lastname: Takahashi
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Terao
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kasai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Imagawa
mesh_terms: D006017:Glycolipids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008050:Lipid A / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors*; D051218:Lymphocyte Antigen 96 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D013329:Structure-Activity Relationship; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014199:Trehalose / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C579729:6,6'-bis-O-(3-nonyldodecanoyl)-alpha,alpha'-trehalose; D006017:Glycolipids; C495377:LY96 protein, human; D008050:Lipid A; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014199:Trehalose