Synthetic Heparan Sulfate-like Oligosaccharides as Tools to Decipher Growth Factor Recognition

Abstract Heparan sulfate proteoglycans (HSPGs) facilitate interactions between growth factors and their receptors, regulating signaling pathways involved in angiogenesis and cell proliferation. However, the structural heterogeneity and synthetic inaccessibility of native heparan sulfate (HS) have limited systematic exploration of structure–activity relationships (SAR) and the discovery of HS-based inhibitors. Here, we developed 46 aminoglycoside-derived non-native HS mimetics spanning diverse structural and functional group patterns. SAR analysis identified N-acetylation and 6-O-sulfation as key determinants of HS-FGF2 and HS–VEGF165 interaction modulation. Compound 8, synthesized in two steps, competitively disrupted heparin binding to FGF2 (IC50 = 0.23 μM), FGFR1 (IC50 = 0.17 μM), and VEGF165 (IC50 = 0.66 μM), with >140-fold FGF2/FGF4 selectivity and substantially greater potency than native HS pentasaccharide fondaparinux. In NIH3T3 fibroblasts, compound 8 selectively reduced FGF2-induced proliferation in a dose-dependent manner without measurable cytotoxicity, highlighting aminoglycoside-derived HS mimetics as synthetically accessible platforms for modulating growth factor signaling.