NOVEL VEGF SUPERAGONISTS/SUPERANTAGONISTS FOR DIABETES

描述：（改编自申请人的摘要）许多证据 提示糖尿病视网膜、肾脏和 神经系统由于局部血管生成增加引起的异常血管生成而导致 缺氧引起的血管内皮生长因子（VEGF）表达， 高血糖和异常糖化。其他证据表明， 心脏和四肢的糖尿病大血管疾病是由 这些组织中VEGF表达或作用受损，阻止了适当的 大血管对动脉粥样硬化的代偿性新生血管反应。 动物模型的初步研究表明，局部抑制VEGF 表达以及抑制其作用可以改善微血管 并发症，而初步研究与局部输送外源性VEGF 在动物和冠状动脉疾病患者中， 新血管形成和症状缓解。很明显，无论是治疗 这两种VEGF激动剂的开发将大大增强这种方法， 以及增加效力和功效的拮抗剂。研究者已 先前开发的糖蛋白激素促甲状腺激素的超激动剂 和促性腺激素，与受体的结合大大增加， 和体内生物活性，使用基于结构的合理类似物策略， 设计以增加配体和受体之间的静电相互作用。在 初步研究表明，这些相同的原则适用于 VEGF，其是胱氨酸结生长因子的结构相关成员 超家族初步假设驱动的VEGF突变已经 导致类似物具有比以前更大的受体结合亲和力 由制药公司使用非定向诱变实现。的 研究者建议通过进一步的方法开发更好的超激动剂， 诱变和确定突变的最佳组合。他还提议 开发具有大大增加的受体结合的VEGF超级拮抗剂， 将一个单体中的这些突变与另一个远端位点的其他突变结合， 另一种连接的单体，其破坏受体二聚化和信号传导 转导此类VEGF超激动剂和超拮抗剂应具有许多优点。 糖尿病并发症的基础科学和治疗应用。

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.