Structural Insights Into The Modulation Of Pdgf/Pdgfr-Beta Complexation By Hyaluronan Derivatives

Angiogenesis is an important physiological process playing a crucial role in wound healing and cancer progression. Vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) are key players in angiogenesis. Based on previous findings regarding the modulation of VEGF activity by glycosaminoglycans (GAG), here we explore the interaction of hyaluronan (HA)-based GAG with PDGF and its receptor PDGFR-beta by applying molecular modeling and dynamics simulations in combination with surface plasmon resonance (SPR). Computational analysis on the interaction of oligo-hyaluronan derivatives with different sulfation pattern and functionalization shows that these GAG interact with PDGF in relevant regions for receptor recognition, and that high sulfation as well as modification with the TAMRA group convey stronger binding. On the other hand, the studied oligohyaluronan derivatives are predicted to scarcely recognize PDGFR-beta. SPR results are in line with the computational predictions regarding the binding pattern of HA tetrasaccharide (HA4) derivatives to PDGF and PDGFR-beta. Furthermore, our experimental results also show that the complexation of PDGF to PDGFR-beta can be modulated by HA4 derivatives. The results found open the path for considering HA4 derivatives as potential candidates to be exploited formodulation of the PDGF/PDGFR-beta signaling systemin angiogenesis and related disease conditions.