Multivalent self-assembling fibroblast growth factor-1-based molecular probe with high affinity for HSPGs and potential antiviral activity

Heparan sulfate proteoglycans (HSPGs) are sulfated glycoconjugates broadly distributed at the plasma membrane and throughout the extracellular matrix. Through interactions mediated by heparan sulfate (HS) chains, these molecules participate in multiple cellular mechanisms, including ligand internalization and regulation of signaling pathways. Aberrant abundance and remodeling of HSPGs have been associated with several pathological conditions, particularly malignant transformation, making them attractive targets for diagnostic and therapeutic applications. Fibroblast growth factors (FGFs) belong to a group of endogenous HS-binding proteins that associate with HSPGs and fibroblast growth factor receptors (FGFRs) during signal initiation. In the present study, we utilized the HS-recognition properties of FGF1 to generate a multivalent protein probe directed toward HSPGs. Controlled oligomerization of FGF1 mutant deficient in FGFR binding with improved HS affinity was achieved using an engineered streptavidin platform that enabled assembly of a tetrameric FGF1-based complex. The resulting construct displayed defined architecture, preserved structural stability and markedly improved interaction with HSPG-containing targets. Our data suggest that this multivalent FGF1-derived biosensor may block interaction of growth factors and viral proteins with HSPGs.