Studies on selectin blockers. 4. Structure-function relationships of sulfated sialyl Lewis X hexasaccharide ceramides toward E-, P-, and L- selectin binding

Kohichiro Yoshino, Hiroshi Ohmoto, Noriko Kondo, Hideki Tsujishita, Yasuyuki Hiramatsu, Yoshimasa Inoue, Hirosato Kondo, Hideharu Ishida, Makoto Kiso, Akira Hasegawa

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

In order to clarify the real ligand structure of L-selectin proposed by Rosen et al., we first synthesized 6-sulfated sLe(x) hexasaccharide ceramide 1, 6'-sulfated sLe(x) hexasaccharide ceramide 2, and 6,6'-disulfated sLe(x) hexasaccharide ceramide 3 and examined their binding avidities for L- selectin. As a result, we found that the 6'-sulfated sLe(x) hexasaccharide ceramides 1-3 have similar binding avidities to L-selectin and their binding to L-selectin appeared somewhat stronger than that of sLe(x). For P-selectin, the sulfated sLe(x) derivatives 1-3 showed a similar avidity to sLe(x). On the other hand, 6-sulfated sLe(x) 2 was recognized to E-selectin and the binding avidity was apparently weak as compared to that of sLe(x) hexasaccharide ceramide. Surprisingly, 6'-sulfated and 6,6'-disulfated sLe(x)s 1 and 3 did not bind to E-selectin at all. We constructed the E- selectin-sLe(x) complex model and investigated the binding mode. Namely, the galactose 6'-position was directed toward the negatively charged residues, Glu80 and ASp100. Our results with E-selectin indicate that the replacement of 6'-OH position from anionic charged group to cationic charged one, e.g., amino groups, could have a marked affect on E-selectin recognition. These results could provide useful information for the drug design of selectin blockers.

Original languageEnglish
Pages (from-to)455-462
Number of pages8
JournalJournal of Medicinal Chemistry
Volume40
Issue number4
DOIs
Publication statusPublished - Feb 14 1997
Externally publishedYes

Fingerprint

L-Selectin
Selectins
P-Selectin
E-Selectin
Drug Design
Galactose
ceramide hexasaccharide
Ligands

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Studies on selectin blockers. 4. Structure-function relationships of sulfated sialyl Lewis X hexasaccharide ceramides toward E-, P-, and L- selectin binding. / Yoshino, Kohichiro; Ohmoto, Hiroshi; Kondo, Noriko; Tsujishita, Hideki; Hiramatsu, Yasuyuki; Inoue, Yoshimasa; Kondo, Hirosato; Ishida, Hideharu; Kiso, Makoto; Hasegawa, Akira.

In: Journal of Medicinal Chemistry, Vol. 40, No. 4, 14.02.1997, p. 455-462.

Research output: Contribution to journalArticle

Yoshino, Kohichiro ; Ohmoto, Hiroshi ; Kondo, Noriko ; Tsujishita, Hideki ; Hiramatsu, Yasuyuki ; Inoue, Yoshimasa ; Kondo, Hirosato ; Ishida, Hideharu ; Kiso, Makoto ; Hasegawa, Akira. / Studies on selectin blockers. 4. Structure-function relationships of sulfated sialyl Lewis X hexasaccharide ceramides toward E-, P-, and L- selectin binding. In: Journal of Medicinal Chemistry. 1997 ; Vol. 40, No. 4. pp. 455-462.
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abstract = "In order to clarify the real ligand structure of L-selectin proposed by Rosen et al., we first synthesized 6-sulfated sLe(x) hexasaccharide ceramide 1, 6'-sulfated sLe(x) hexasaccharide ceramide 2, and 6,6'-disulfated sLe(x) hexasaccharide ceramide 3 and examined their binding avidities for L- selectin. As a result, we found that the 6'-sulfated sLe(x) hexasaccharide ceramides 1-3 have similar binding avidities to L-selectin and their binding to L-selectin appeared somewhat stronger than that of sLe(x). For P-selectin, the sulfated sLe(x) derivatives 1-3 showed a similar avidity to sLe(x). On the other hand, 6-sulfated sLe(x) 2 was recognized to E-selectin and the binding avidity was apparently weak as compared to that of sLe(x) hexasaccharide ceramide. Surprisingly, 6'-sulfated and 6,6'-disulfated sLe(x)s 1 and 3 did not bind to E-selectin at all. We constructed the E- selectin-sLe(x) complex model and investigated the binding mode. Namely, the galactose 6'-position was directed toward the negatively charged residues, Glu80 and ASp100. Our results with E-selectin indicate that the replacement of 6'-OH position from anionic charged group to cationic charged one, e.g., amino groups, could have a marked affect on E-selectin recognition. These results could provide useful information for the drug design of selectin blockers.",
author = "Kohichiro Yoshino and Hiroshi Ohmoto and Noriko Kondo and Hideki Tsujishita and Yasuyuki Hiramatsu and Yoshimasa Inoue and Hirosato Kondo and Hideharu Ishida and Makoto Kiso and Akira Hasegawa",
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T1 - Studies on selectin blockers. 4. Structure-function relationships of sulfated sialyl Lewis X hexasaccharide ceramides toward E-, P-, and L- selectin binding

AU - Yoshino, Kohichiro

AU - Ohmoto, Hiroshi

AU - Kondo, Noriko

AU - Tsujishita, Hideki

AU - Hiramatsu, Yasuyuki

AU - Inoue, Yoshimasa

AU - Kondo, Hirosato

AU - Ishida, Hideharu

AU - Kiso, Makoto

AU - Hasegawa, Akira

PY - 1997/2/14

Y1 - 1997/2/14

N2 - In order to clarify the real ligand structure of L-selectin proposed by Rosen et al., we first synthesized 6-sulfated sLe(x) hexasaccharide ceramide 1, 6'-sulfated sLe(x) hexasaccharide ceramide 2, and 6,6'-disulfated sLe(x) hexasaccharide ceramide 3 and examined their binding avidities for L- selectin. As a result, we found that the 6'-sulfated sLe(x) hexasaccharide ceramides 1-3 have similar binding avidities to L-selectin and their binding to L-selectin appeared somewhat stronger than that of sLe(x). For P-selectin, the sulfated sLe(x) derivatives 1-3 showed a similar avidity to sLe(x). On the other hand, 6-sulfated sLe(x) 2 was recognized to E-selectin and the binding avidity was apparently weak as compared to that of sLe(x) hexasaccharide ceramide. Surprisingly, 6'-sulfated and 6,6'-disulfated sLe(x)s 1 and 3 did not bind to E-selectin at all. We constructed the E- selectin-sLe(x) complex model and investigated the binding mode. Namely, the galactose 6'-position was directed toward the negatively charged residues, Glu80 and ASp100. Our results with E-selectin indicate that the replacement of 6'-OH position from anionic charged group to cationic charged one, e.g., amino groups, could have a marked affect on E-selectin recognition. These results could provide useful information for the drug design of selectin blockers.

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