: Heparin and heparan sulfate (HS) glycosaminoglycans (GAGs) are essential regulators of neurotrophic signaling. However, their therapeutic applications are hindered by structural heterogeneity, batch variability, and anticoagulant activity. Thus, there is a need for well-defined glycomimetics that replicate the function of native HS in regenerative medicine. Here, we synthesized HS glycomimetics through a modular strategy that enables the installation of sulfate groups at the designated positions along the sugar backbone. These glycomimetics selectively bind and stabilize neurotrophins, such as fibroblast growth factors (FGF-1, FGF-2) and nerve growth factor (NGF), in a sulfation-dependent manner with dissociation constants in the low micromolar range. They exhibit no anticoagulant activity, a crucial prerequisite for clinical translation. We show that our lead compound has neuritogenic ability because in two neuronal cell models, PC12 and SH-SY5Y, it enhances NGF-mediated neural maturation when immobilized on a surface. Furthermore, in primary rat hippocampal neurons, it promotes FGF-2-mediated neurite outgrowth and spontaneous synaptic activity. Our findings show that HS glycomimetics have the potential for regenerative therapies.
