Journal Article

P-Selectin Inhibition and the Structure–Activity Relationship of Sea Cucumber-Derived Fucosylated Glycosaminoglycan Oligosaccharides

Yin, Ronghua, Li, Sujuan, Lin, Lisha, Zeng, Chunyu, Yang, Lian, Zhao, Jinhua, Gao, Na, Pan, Ying

2026

Overview

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.

• Publisher: MDPI AG,Multidisciplinary Digital Publishing Institute (MDPI)
• Subject: Acids / Affinity / Analysis / Animals / Anticoagulants / Binding / Care and treatment / Cell adhesion molecules / Chondroitin sulfate / Clinical trials / Competition / Control / Disaccharides / Drug development / Drugs / Endothelial cells / FDA approval / Fucose - chemistry / fucosylated glycosaminoglycan / Glycan / Glycosaminoglycans / Glycosaminoglycans - chemistry / Glycosaminoglycans - pharmacology / Glycosylation / Health aspects / Holothurians / Humans / Immune system / Inflammation / inflammatory diseases / Interferometry / Leukocytes / Ligands / Marine invertebrates / Molecular weight / Monoclonal antibodies / oligosaccharide / Oligosaccharides / Oligosaccharides - chemistry / Oligosaccharides - pharmacology / P-selectin / P-Selectin - antagonists & inhibitors / P-Selectin - metabolism / P-selectin inhibitor / Physiological aspects / Polymerization / Sea Cucumbers - chemistry / Structure-Activity Relationship / Structure-activity relationship (Pharmacology) / Structure-activity relationships / Sulfation / Testing / Therapeutic targets