The selectin family constitutes a well-known class of immune-regulatory molecules, among which P-selectin has emerged as a therapeutic target for inflammatory thrombotic diseases due to its capacity to mediate the adhesion between multiple immune cell subsets and endothelial cells. Currently, small-molecule or glycomimetic inhibitors targeting P-selectin have stalled in Phase III clinical trials, with a common limitation being their weak binding affinity to P-selectin. In this study, in vitro competitive binding assays were employed to evaluate the inhibitory effects of structurally distinct fucosylated glycosaminoglycan (FG) oligosaccharides, derived from sea cucumbers, on the interaction between P-selectin and its ligands. A potent inhibitor, the nonasaccharide Ta-9-2 (featuring a novel disaccharide side chain), was identified. Biolayer interferometry (BLI) analysis further confirmed its high binding affinity to P-selectin, with a KD of 83.92 nM. Structure–activity relationship (SAR) analysis reveals that the appropriate glycan chain length, the novel disaccharide side chain (Gal4S6S-α1,2-L-Fuc3S-α1,3), and the favorable sulfation pattern (Fuc2S4S) serve as the molecular basis for potent P-selectin inhibition. This study provides a robust theoretical foundation for the structural optimization of glycomimetic targeting P-selectin, while also offering a new opportunity for the development of high-efficacy drug candidates.
Li et al. (Thu,) studied this question.
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