Carbohydr Polym 2025 Nov 01;375:124752. doi: 10.1016/j.carbpol.2025.124752.

Structure-activity relationship of a potent anti-FXase and antithrombotic chondroitin sulfate-dermatan sulfate hybrid bearing 2,3-O-sulfated motifs from Anthenoides laevigatus.

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This study isolated a homogeneous polysaccharide ALHX-2M from the body wall of the starfish Anthenoides laevigatus (South China Sea). Structural characterization identified it as a chondroitin sulfate-dermatan sulfate (CS-DS) hybrid chain with a 38.53 % sulfate content and unique 2,3-di-O-sulfate motifs, mainly constituted by the repeating disaccharide units -L-IdoA2S3S-α1,3-D-GalNAc4S(6S)-β1,4- and -D-GlcA2S3S-β1,3-D-GalNAc4S-β1,4- disaccharide with a molar ratio of approximately 2:1. ALHX-2M potently inhibited the intrinsic and common coagulation pathway, as evidenced by significantly prolonged APTT/TT without affecting PT. In vivo, 1.8 mg/kg ALHX-2M achieved 89.7 % thrombus inhibition in tissue thromboplastin-induced rat venous thrombosis (equivalent to 3.6 mg/kg LMWH) and exhibited strong efficacy in carrageenan-induced mouse tail thrombosis, with significantly lower bleeding risk than LMWH. It displayed potent FXase inhibition (IC50 = 57.1 ± 9.3 ng/mL, three-fold more potent than LMWH) and bound FIXa, a serine protease integral to the FXase complex, with high affinity (KD = 2.47 × 10-9 M). Structure-activity relationships confirmed: (1) activity requires a critical molecular size; (2) sulfate groups are essential; and (3) carboxyl groups are critical for FXase targeting. This unusual CS-DS hybrid chain represents a novel low-bleeding-risk anticoagulant candidate, providing an experimental basis for marine antithrombotic drug development and South China Sea biological resource utilization.

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