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

J Med Chem. 1997 Feb 14;40(4):455-62. doi: 10.1021/jm9605290.

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.

MeSH terms

  • Animals
  • Ceramides / chemistry
  • Ceramides / metabolism*
  • Drug Design
  • E-Selectin / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • L-Selectin / metabolism
  • Lewis Blood Group Antigens / metabolism*
  • Models, Chemical
  • Oligosaccharides / metabolism*
  • P-Selectin / metabolism
  • Rats
  • Selectins / metabolism*
  • Sialyl Lewis X Antigen
  • Software
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfates*

Substances

  • Ceramides
  • E-Selectin
  • Lewis Blood Group Antigens
  • Oligosaccharides
  • P-Selectin
  • Selectins
  • Sialyl Lewis X Antigen
  • Sulfates
  • L-Selectin