NOVEL VEGF SUPERAGONISTS/SUPERANTAGONISTS FOR DIABETES

描述：(改编自申请人的摘要)多行证据 提示糖尿病视网膜、肾脏和肾脏的微血管并发症 神经系统由局部血管生成增加引起的异常血管生成引起 低氧对血管内皮生长因子表达的影响 高血糖和糖化异常。其他方面的证据表明 糖尿病心脏和四肢的大血管疾病因 这些组织中的血管内皮生长因子的表达或作用受损，阻止适当的 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，局部抑制血管内皮生长因子 表达和抑制其作用可能改善微血管 局部注射外源性血管内皮细胞生长因子的并发症 在动物和冠心病患者中显示出有益的 新生血管和缓解症状。很明显，这两种疗法 这两种血管内皮生长因子激动剂的开发将极大地促进这些方法的发展 以及增强效力和疗效的拮抗剂。调查员已经 先前开发的糖蛋白激素促甲状腺激素的超级激动剂 和促性腺激素，大大增加了与受体的结合，并在体外 以及使用基于结构的有理类似物策略的体内生物活性 设计以增加配体和受体之间的静电相互作用。在……里面 初步研究表明，这些原则同样适用于 血管内皮生长因子，它是胱氨酸结生长因子中结构上相关的成员 超级大家庭。初步假说驱动的血管内皮生长因子突变已经 使类似物具有比以前更强的受体结合亲和力 由制药公司使用非定向突变实现。这个 研究人员建议通过进一步开发更多改进的超级激动剂 诱变和确定最佳的突变组合。他还建议 开发受体结合力显著提高的血管内皮生长因子超拮抗剂 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在一起 另一种破坏受体二聚和信号的连接单体 转导。这样的血管内皮生长因子超级激动剂和超级拮抗剂应该有很多 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.