Protein Engineering Receptor Antagonist

Our primary goal is to inhibit the angiogenic process through the specific antagonism of a growth finteraction. Although an absolute requirement for the proper development of a growing fetus, angiogebeen associated with numerous disease states, including the growth of solid tumors, diabetic retinoparthritis and psoriasis. Recently, a direct link between angiogenesis and tumor metastasis has beenemphasizing the need for novel pharmaceuticals that specifically regulate angiogenesis. Among the momediators of angiogenesis are members of the fibroblast growth factor (FGF) family. Monomeric FGF inreceptors (FGFR) and heparan sulfate proteoglycans in a highly specific manner on cell surfaces thatdimerization, thus initiating the signal transduction cascade resulting in cell proliferation. We wiFGF with its cognate receptor by employing a protein structure an mechanism based approach in whichwill prevent FGFR dimerization. This will be accomplished through the modification of receptor bindisite-directed mutagenesis. A second component of this proposal will be the development of a more potaccomplished by enhancing the binding affinity of FGF to FGFR by protein structure- based site-direcFGFs are also potent mediators of the wound healing process and formulations of FGF are currently inaccelerate the healing process. A more potent FGF would serve to decrease the amount of protein requsame therapeutic result.