Rationally designed tetrasaccharide inhibitors of heparanase with anti-inflammatory activity and protective effects in sepsis

  • Eur J Med Chem. 2026 Jun 22:317:119076. doi: 10.1016/j.ejmech.2026.119076.
Yu Zhou  1 ,  Ke Feng  1 ,  Hongzhen Jin  2 ,  Haoyu Xue  3 ,  Yongmei Yin  4 ,  Kaixuan Wang  5 ,  Wei Zhao  6
Affiliations
  • 1. State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tianjin, 300350, China.
  • 2. Qingdao Central Hospital, School of Life Sciences and Health, Qingdao Key Laboratory of Precision Drug Research for Chronic Disease Rehabilitation, University of Health and Rehabilitation Sciences, Qingdao, 266113, China.
  • 3. State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tianjin, 300350, China; Qingdao Central Hospital, School of Life Sciences and Health, Qingdao Key Laboratory of Precision Drug Research for Chronic Disease Rehabilitation, University of Health and Rehabilitation Sciences, Qingdao, 266113, China.
  • 4. State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tianjin, 300350, China. Electronic address: [email protected].
  • 5. State Key Laboratory of Natural and Biomimetic Drugs, New Cornerstone Science Laboratory, Chemical Biology Center, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address: [email protected].
  • 6. State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tianjin, 300350, China; Qingdao Central Hospital, School of Life Sciences and Health, Qingdao Key Laboratory of Precision Drug Research for Chronic Disease Rehabilitation, University of Health and Rehabilitation Sciences, Qingdao, 266113, China. Electronic address: [email protected].
PMID: 42361480 DOI: 10.1016/j.ejmech.2026.119076
Abstract

Sepsis is a life-threatening disorder with high mortality and limited host-targeted treatments. Heparanase (HPA) mediates endothelial glycocalyx degradation and represents a key therapeutic target for sepsis. Our previously reported pentasaccharide CV122 showed potent HPA inhibition and anti-inflammatory efficacy, yet its complex structure, dense sulfation, and low synthetic yield hindered further development. Herein, we rationally designed and synthesized a series of structurally defined sulfated tetrasaccharides by truncating and optimizing the CV122 scaffold. Compound 5 displayed the most potent HPA inhibition with an IC50 of 11.27 μM. In a Cecal Ligation and Puncture (CLP) induced mouse sepsis model, compound 5 significantly improved survival, reduced pro-inflammatory cytokines, and preserved organ morphology. Molecular docking confirmed favorable binding to the HPA active site. This work showed that rationally modified tetrasaccharides derived from CV122 retained strong inhibitory activity with better synthetic accessibility, offering a promising glycan-based strategy for sepsis intervention.

Keywords
Anti-inflammatory activity; Glycocalyx protection; Heparanase inhibitors; Sepsis; Sulfated tetrasaccharide.
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