NOVEL VEGF SUPERAGONISTS/SUPERANTAGONISTS FOR DIABETES

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DESCRIPTION: (Adapted from the applicant's abstract) Many lines of evidence suggest that diabetic microvascular complications in the retina, kidney and nervous system result from aberrant angiogenesis caused by increased local expression of vascular endothelial growth factor (VEGF) resulting from hypoxia, hyperglycemia and abnormal glycation. Other lines of evidence suggest that diabetic macrovascular disease in the heart and limbs is accentuated by impaired VEGF expression or action in these tissues, preventing an appropriate compensatory neovascularization response to atherosclerosis in large vessels. Preliminary studies in animal models suggest that local inhibition of VEGF expression as well as inhibition of its action may improve microvascular complications while preliminary studies with local delivery of exogenous VEGF in animals and patients with coronary artery disease has shown beneficial neovascularization and relief of symptoms. It is clear that both therapeutic approaches would be greatly enhanced by the development of both VEGF agonists and antagonists of increased potency and efficacy. The investigator has previously developed superagonists of the glycoprotein hormones, thyrotropin and gonadotropin, with greatly increased binding to the receptor and in vitro and in vivo bioactivity using a structurally based strategy of rational analog design to increase electrostatic interactions between ligand and receptor. In preliminary studies, the investigator shows that these same principles apply to VEGF, which is a structurally related member of the cystine knot growth factor superfamily. Preliminary hypothesis-driven mutagenesis of VEGF has already results in analogs with much greater receptor binding affinity than previously achieved by pharmaceutical companies using non-directed mutagenesis. The investigator proposes to develop even more improved superagonists by further mutagenesis and determining optimal combinations of mutations. He also proposes to develop VEGF superantagonists with greatly increased receptor binding by combining these mutations in one monomer with others at another distant site in another linked monomer which disrupts receptor dimerization and signal transduction. Such VEGF super-agonists and super antagonists should have many basic science and therapeutic applications for diabetes complications.