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

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.