Development of Apo Mimetic Peptides for the Treatment Cardiovascular Disease

我们实验室早些时候已经证明，5A两亲肽可以通过ABCA1转运体特异性去除胆固醇，在过去的一年里，我们在几个动物模型中进行了测试。通过兔颈圈模型，发现5A肽可降低内皮细胞黏附分子的表达，减少炎症细胞向血管壁的浸润。当小鼠接受单次静脉注射5A肽时，它会升高HDL-C，并增加血清从细胞中去除多余胆固醇的能力。此外，还发现5A肽可以动员外周组织中的胆固醇，增加粪便中胆固醇的排泄。研究发现，长期治疗该肽可显著降低载脂蛋白e基因敲除小鼠的动脉粥样硬化，这表明它可能是一种替代载脂蛋白a - i输注治疗的可能选择。对两亲肽家族（即ELK肽）的结构功能研究表明，某些结构基序与其体外生物学特性相关。在未来，ELK肽的体外特性将与它们对小鼠动脉粥样硬化模型的影响进行比较，为设计模拟载脂蛋白肽提供更好的理论依据。

The 5A amphipathic peptide, which was shown earlier by our laboratory to be specific for removing cholesterol by the ABCA1 transporter, was tested in the past year in several animal models. Using a rabbit collar model, the 5A peptide was found to reduce the expression of adhesion molecules on endothelial cells and reduce the infiltration of inflammatory cells into the vessel wall. When mice were treated with a single IV bolus of the 5A peptide, it raised HDL-C and increased the capacity of serum for removing excess cholesterol from cells. Furthermore, the 5A peptide was found to mobilize cholesterol from peripheral tissues and increase fecal cholesterol excretion. Long term treatment of the peptide was found to markedly reduce atherosclerosis in apoE knokout mice, indicating that it may be a possible alternative to using apolipoprotein A-I for HDL infusion therapy. Structure-function studies of a family of amphipathic peptides referred to as ELK peptides revealed that certain structural motifs correlated with their in vitro biological properties. In the future, the in vitro properties of the ELK peptides will be compared to their effect on mouse models of atherosclerosis to provide a better rationale in the design of apolipoprotien mimetic peptides.