Development of Apolipoprotein-based Therapeutics for Asthma

载脂蛋白E是一种34 kDa、299个氨基酸的蛋白质，折叠成螺旋马蹄形结构，它包含一个独特的低密度脂蛋白受体结合域，对应于氨基端的134到150个氨基酸，以及一个主要的脂结合域，对应于羧基末端的244到272个氨基酸。载脂蛋白E的氨基末端由四个两亲性的α-螺旋组成，低密度脂蛋白受体结合区位于螺旋4。与低密度脂蛋白受体结合域相对应的载脂蛋白E模拟肽被证明能与低密度脂蛋白受体家族成员结合，从而抑制炎症和神经毒性，并介导抗病毒作用。我们已经证明，全身注射载脂蛋白E模拟肽，对应于全长蛋白的130-149个氨基酸，可以挽救apoE基因敲除小鼠的哮喘表型，并减弱室内尘螨诱导的哮喘的诱导(载脂蛋白E通过低密度脂蛋白受体介导的途径负面调节室内尘螨诱导的哮喘)。姚X，弗雷德里克森·K，于正欣，徐翔，拉加瓦查里·N，基兰·KJ，Zywicke GJ，Kwak M，Amar MJ，Remaley AT，Levine SJ。Am J Respir CRUT CARE Med。2010年7月9日，印刷前的ePub)。正在进行的项目正在进一步确定载脂蛋白E和载脂蛋白A-I模拟肽作为治疗哮喘的潜在新方法的作用。该项目产生的临床前数据显示了雾化吸入肺部的效果，将用于支持这种方法在严重哮喘患者中的未来临床试验。

Apolipoprotein E is a 34 kDa, 299 amino acid protein that folds into a helical horseshoe configuration which contains a distinct LDL receptor-binding domain, corresponding to amino acids 134 to 150 of the amino-terminus, as well as a major lipid-binding domain, corresponding to amino acids 244 to 272 of the carboxy-terminus. The amino-terminus of apolipoprotein E is comprised of a four amphipathic alpha-helices, with the LDL receptor-binding domain located in helix 4. Apolipoprotein E mimetic peptides, which correspond to the LDL receptor-binding domain, have been shown to bind LDL receptor family members and thereby suppress inflammation and neurotoxicity, as well as to mediate anti-viral effects. We have demonstrated that systemic administration of an apolipoprotein E mimetic peptide, corresponding to amino acids 130 149 of the full-length protein, can rescue the asthmatic phenotype of apoE knockout mice and attenuate the induction of house dust mite-induced asthma (Apolipoprotein E Negatively Regulates House Dust Mite-induced Asthma via a LDL Receptor-mediated Pathway. Yao X, Fredriksson K, Yu ZX, Xu X, Raghavachari N, Keeran KJ, Zywicke GJ, Kwak M, Amar MJ, Remaley AT, Levine SJ. Am J Respir Crit Care Med. 2010 Jul 9. Epub ahead of print). Ongoing projects are further defining the role of apolipoprotein E and apolipoprotein A-I mimetic peptides as a potential new therapeutic approach for asthma. The pre-clinical data generated from this project demonstrating the efficacy of aerosolized delivery to the lung will be used to support future clinical trials of this approach in patients with severe asthma.