Synthetic glycoprotein mimics inhibit L-selectin-mediated rolling and promote L-selectin shedding.
L-selectin is a leukocyte cell-surface protein that facilitates the rolling of leukocytes along the endothelium, a process that leads to leukocyte migration to a site of infection. Preventing L-selectin-mediated rolling minimizes leukocyte adhesion and extravasation; therefore, compounds that inhibit rolling may act as anti-inflammatory agents. To investigate the potential role of multivalent ligands as rolling inhibitors, compounds termed neoglycopolymers were synthesized that possess key structural features of physiological L-selectin ligands. Sulfated neoglycopolymers substituted with sialyl Lewis x derivatives (3',6-disulfo Lewis x or 6-sulfo sialyl Lewis x) or a sulfatide analog (3,6-disulfo galactose) inhibited L-selectin-mediated rolling of lymphoid cells. Functional analysis of the inhibitory ligands indicates that they also induce proteolytic release of L-selectin. Thus, their inhibitory potency may arise from their ability to induce shedding. Our data indicate that screening for compounds that promote L-selectin release can identify ligands that inhibit rolling.
Mowery
Patricia
P
Department of Biochemistry, 433 Babcock Drive, University of Wisconsin-Madison, Madison, WI 53706 USA.
Yang
Zhi-Qiang
ZQ
Gordon
Eva J
EJ
Dwir
Oren
O
Spencer
Andrew G
AG
Alon
Ronen
R
Kiessling
Laura L
LL
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002240:Carbohydrate Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006023:Glycoproteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D019041:L-Selectin / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D036904:Leukocyte Rolling / Q000187:drug effects*; D008024:Ligands; D008214:Lymphocytes / Q000187:drug effects; D051379:Mice; D018716:Molecular Mimicry; D008969:Molecular Sequence Data
D000893:Anti-Inflammatory Agents; D006023:Glycoproteins; D008024:Ligands; D019041:L-Selectin