Determination of the Core Sequence of an Antagonist of Selectin-Dependent Leukocyte Adhesion and Correlation of Its Structure with Molecular Modeling Studies

The sequence 36–50 from the lectin domain of human P-selectin has been previously identified as a weak inhibitor of selectin-dependent leukocyte adhesion. A series of C- and N-terminally truncated peptides was synthesized to determine the limits of the active core region within the parent sequence. Deletions from both the N- and C-termini gave significant increases in inhibitory activity and identified 41–50 or 36–49 as minimum active sequences, but surprisingly not the common 41–49 peptide. All peptides tested showed parallel inhibition of both P- and E-selectin-dependent adhesion. A molecular model of the lectin domain was constructed using homology modeling. Examination of this model suggests one hypothesis to explain the increase in activity on deletion of Asp36.