Chemical structure of PSS 
 
 

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ABSTRACT

 
Basic Fibroblast Growth Factor (FGF-2) interacts with high affinity tyrosine-kinase receptors (FGFRs) and low affinity heparan sulfate proteoglycans (HSPGs) in target cells. Both interactions are required for FGF-2-mediated biological responses. 

We here report the FGF-2 antagonist activity of novel synthetic sulfonic acid polymers with distinct chemical structures and molecular weights (MWs). PAMPS [poly(2-acrylamido-2-methyl-1-propanesulfonic acid)], (MW»7,000-10,000), PAS [poly(anetholesulfonic acid)], (MW»9,000-11,000), PSS [poly(4-styrenesulfonic acid)], (MW=70,000), and PVS [poly(vinylsulfonic acid)], (MW=2,000) inhibited FGF-2 binding to HSPGs and FGFRs in fetal bovine aortic endothelial GM 7373 cells. 

They also abrogated the formation of the HSPG/FGF-2/FGFR ternary complex, as evidenced by their capacity to prevent FGF-2-mediated cell-cell attachment of FGFR-1-overexpressing, HSPG-deficient CHO cells to wild-type HSPG-bearing cells. 

Direct interaction of the polysulfonates with FGF-2 was demonstrated by their ability to protect the growth factor from proteolytic cleavage. Accordingly, molecular modeling, based on the crystal structure of the interaction of FGF-2 with a heparin hexamer, showed the feasibility of docking PAMPS into the heparin-binding domain of FGF-2. 

In agreement with their FGF-2-binding capacity, PSS, PAS, and PAMPS inhibited FGF-2-induced cell proliferation in GM 7373 cells and murine brain microvascular endothelial (MBE) cells. The anti-proliferative activity of these compounds was associated with the abrogation of FGF-2-induced tyrosine phosphorylation of FGFR-1. Moreover, the polysulfonates PSS and PAS inhibited FGF-2-induced activation of mitogen-activated protein kinase-1/2 (ERK-1/2), involved in FGF-2 signal transduction. 

In conclusion, sulfonic acid polymers bind FGF-2 by mimicking heparin interaction. These compounds may provide a tool to inhibit FGF-2-induced endothelial cell proliferation in angiogenesis and tumor growth.
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Mol. Pharmacol. (1999) 56, 204-213.