title: Identification of the optimal structure required for a Shiga toxin neutralizer with oriented carbohydrates to function in the circulation.
abstract: Shiga toxin (Stx) is a major virulence factor of Stx-producing Escherichia coli. Recently, we developed a therapeutic Stx neutralizer with 6 trisaccharides of globotriaosyl ceramide, a receptor for Stx, in its dendrimer structure (referred to as "SUPER TWIG [1]6") to function in the circulation. Here, we determined the optimal structure of SUPER TWIG for it to function in the circulation and identified a SUPER TWIG with 18 trisaccharides, SUPER TWIG (2)18, as another potent Stx neutralizer. SUPER TWIGs (1)6 and (2)18 shared a structural similarity, a dumbbell shape in which 2 clusters of trisaccharides were connected via a linkage with a hydrophobic chain. The dumbbell shape was found to be required for formation of a complex with Stx that enables efficient uptake and degradation of Stx by macrophages and, consequently, for potent Stx-neutralizing activity in the circulation. We also determined the binding site of the SUPER TWIGs on Stx.
authors.affiliation: Department of Clinical Pharmacology, Research Institute, International Medical Center of Japan, Tokyo, Japan. knishika@ri.imcj.go.jp
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Nishikawa
authors.forename: Koji
authors.initials: K
authors.lastname: Matsuoka
authors.forename: Miho
authors.initials: M
authors.lastname: Watanabe
authors.forename: Katsura
authors.initials: K
authors.lastname: Igai
authors.forename: Kumiko
authors.initials: K
authors.lastname: Hino
authors.forename: Ken
authors.initials: K
authors.lastname: Hatano
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yamada
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Abe
authors.forename: Daiyo
authors.initials: D
authors.lastname: Terunuma
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Kuzuhara
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Natori
mesh_terms: D000818:Animals; D002236:Carbohydrate Conformation; D002241:Carbohydrates / Q000737:chemistry* / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D015195:Drug Design; D004926:Escherichia coli; D005260:Female; D007700:Kinetics; D051379:Mice; D008813:Mice, Inbred ICR; D011485:Protein Binding; D021122:Protein Subunits; D022621:Shiga Toxin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013997:Time Factors; D014709:Vero Cells
chemical_list: D002241:Carbohydrates; D021122:Protein Subunits; D022621:Shiga Toxin