Identification of the optimal structure required for a Shiga toxin neutralizer with oriented carbohydrates to function in the circulation.
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.
Nishikawa
Kiyotaka
K
Department of Clinical Pharmacology, Research Institute, International Medical Center of Japan, Tokyo, Japan. knishika@ri.imcj.go.jp
Matsuoka
Koji
K
Watanabe
Miho
M
Igai
Katsura
K
Hino
Kumiko
K
Hatano
Ken
K
Yamada
Akihiro
A
Abe
Nobuhisa
N
Terunuma
Daiyo
D
Kuzuhara
Hiroyoshi
H
Natori
Yasuhiro
Y
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
D002241:Carbohydrates; D021122:Protein Subunits; D022621:Shiga Toxin