ANTI-ANGIOGENIC PEPTIDES DERIVED FROM HUMAN KININOGEN

一个新兴的范例是血浆或细胞外蛋白质的片段可以调节血管生成。一种已知的血浆蛋白最近被鉴定为仅在蛋白水解活化后具有抗血管生成活性。该蛋白质与先前鉴定的具有抗血管生成活性的蛋白质（例如血管抑素、血小板反应蛋白）没有同源性。这种活化的蛋白质与内皮细胞的特异性结合已被证明。这导致在体外抑制内皮细胞增殖（IC 50 = 10 nM）以及在Matrigel Plug模型中抑制体内血管生成。内皮细胞的迁移也受到这种活化蛋白的抑制，IC 50 = 100 nM。已经合成并测试了基于该蛋白质序列的肽，并且已经鉴定了具有抗内皮细胞增殖活性的16-mer肽。该I期提案的目标是鉴定抑制内皮细胞增殖和迁移所需的最小序列，并从活性和稳定性的角度优化这些肽。基于结构的药物设计将用于II期，以基于优化的肽序列开发肽模拟物。阶段II的目标是基于阶段I中鉴定的优化肽的序列鉴定药物候选肽或肽模拟物。拟议的商业应用：病理性血管生成与几种主要的人类疾病状态有关，包括癌症、关节炎、动脉粥样硬化和视网膜病变。我们建议创造一种候选药物，其将特异性地抑制内皮细胞的增殖，并且可以在临床上用作抗血管生成剂。血管生成的治疗靶向已经在体内得到验证，并且可以在急性和慢性使用环境中应用。

An emerging paradigm is that fragments of plasma or extracellular proteins may regulate angiogenesis. A known plasma protein has recently been identified as having anti-angiogenic activity only after proteolytic activation. This protein has no homology to previously identified proteins with anti-angiogenic activity e.g. angiostatin, thrombospondin. The specific binding of this activated protein to endothelial cells has been demonstrated. This results in the inhibition of endothelial cell proliferation in vitro (IC50 = 10 nM) as well as angiogenesis in vivo in a Matrigel Plug model. The migration of endothelial cells is also inhibited by this activated protein with an IC50 = 100 nM. Peptides based on the sequence of this protein have been synthesized and tested and l6-mer peptides with anti- proliferative activity against endothelial cells have been identified. The goal of this Phase I proposal is to identify the minimal sequences required for the inhibition of endothelial cell proliferation and migration and to optimize these peptides from the standpoint of activity and stability. Structure-based drug design will be used in Phase II to develop peptidomimetics based on the optimized peptide sequences. The goal of Phase II will be to identify a drug candidate peptide or peptidomimetic based on the sequence(s) of the optimized peptides identified in Phase I. PROPOSED COMMERCIAL APPLICATIONS: Pathological angiogenesis has been implicated in several major human disease states including cancer, arthritis, atherosclerosis and retinopathy. We propose to create a drug candidate which would specifically inhibit the proliferation of endothelial cells and could be usefii1 clinically as an anti- angiogenic agent. The therapeutic targeting of angiogenesis has been validated in vivo and may have application in both the acute and chronic use setting.