Abstract
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.