The selectins are cell adhesion molecules whose carbohydrate-binding d
omain (C-type lectin) is thought to be involved in leukocyte adhesion
to activated vascular endothelium in the inflammatory process, A serie
s of peptides, based on a conserved region ((48)YYWIGIRK(55)-NH2) of t
he lectin domain of E-, L- and P-selectins, were analysed for their ab
ility to block selectin-mediated cell adhesion in vitro, and neutrophi
l infiltration into sites of inflammation in vivo, The peptides inhibi
ted the adhesion of myeloid cells to recombinant forms of E- and P-sel
ectin, The adhesion of myeloid cells to human endothelial cells, stimu
lated to express E-selectin, was also inhibited by the peptides, Final
ly, the peptides blocked the adhesion of lymphocytes, expressing L-sel
ectin, to high endothelial venules in lymph nodes which contain the li
gand for L-selectin, A clear structure-activity relationship was estab
lished when peptides of different amino acid chain lengths were tested
in these assays, Peptides lacking tyrosine residues (e.g. WIGIR-NH2)
at their amino terminus were poor inhibitors of selectin-mediated cell
adhesion ill vitro, The peptides that were found to be inhibitors of
cell adhesion in vitro were also found to inhibit (up to 70%) neutroph
il infiltration into sites of inflammation in a thioglycollate-induced
peritonitis mouse model system, They also significantly reduced (>50%
) the migration of neutrophils into cytokine-treated skin. These resul
ts strongly suggest that compounds based on these tyrosine-containing,
selectin-derived peptides could be used as anti-inflammatory therapeu
tic agents.