A novel method for oral delivery of apolipoprotein mimetic peptides synthesized from all L-amino acids
A novel method for oral delivery of apolipoprotein mimetic peptides synthesized from all L-amino acids
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DOI：
10.1194/jlr.m800539-jlr200
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发表时间：
2009-08-01
影响因子：
6.5
通讯作者：
Fogelman, Alan M.
中科院分区：
文献类型：
--
作者：
Navab, Mohamad;Ruchala, Piotr;Fogelman, Alan M.
皮下给药，D-4F或L-4F同样有效，但只有D-4F是口服有效的，因为L-4F被肠道蛋白酶消化。在apoE缺失小鼠中，在口服L-4F（但不是单独的氯硝柳胺）的时间附近口服氯硝柳胺（一种氯化水杨酰苯胺，用作杀软体动物剂、驱虫剂和杀lampricide）导致HDL炎症指数（HII）显著改善（P < 0.001），该指数测量HDL抑制内皮细胞培养物中LDL诱导的单核细胞趋化活性的能力。口服L-[113-122]apoJ和氯硝柳胺也导致HII显著改善（P < 0.001）。对9.5月龄的apoE基因敲除雌性小鼠口服氯硝柳胺和L-4F以及普伐他汀6个月，与治疗前相比，主动脉窦病变面积（P = 0.02）、表面病变面积（P = 0.033）和巨噬细胞病变面积（P = 0.02）显著减少，表明病变消退。相比之下，仅接受氯硝柳胺和普伐他汀或L-4F和普伐他汀的小鼠的病变明显更大（P < 0.001）。在体外氯硝柳胺和L-4F紧密结合，使肽对胰蛋白酶消化具有抗性。氯硝柳胺本身不抑制胰蛋白酶活性。氯硝柳胺与载脂蛋白模拟肽的组合似乎是口服递送这些肽的有前途的方法。纳瓦布湾P.，Ruchala，A. J. Waring，R. I.莱勒，S.哈马湾哈，M。N. Palgunachari，G. M. Anantharamaiah和A. M.福格尔曼一种新的口服给药的载脂蛋白模拟肽合成的所有L-氨基酸。J. Lipid Res. 2009. 50：1538-1547。
Administered subcutaneously, D-4F or L-4F are equally efficacious, but only D-4F is orally efficacious because of digestion of L-4F by gut proteases. Orally administering niclosamide (a chlorinated salicylanilide used as a molluscicide, antihelminthic, and lampricide) in temporal proximity to oral L-4F (but not niclosamide alone) in apoE null mice resulted in significant improvement (P < 0.001) in the HDL-inflammatory index (HII), which measures the ability of HDL to inhibit LDL-induced monocyte chemotactic activity in endothelial cell cultures. Oral administration of L-[113-122]apoJ with niclosamide also resulted in significant improvement (P < 0.001) in HII. Oral administration of niclosamide and L-4F together with pravastatin to female apoE null mice at 9.5 months of age for six months significantly reduced aortic sinus lesion area (P = 0.02), en face lesion area (P = 0.033), and macrophage lesion area (P = 0.02) compared with pretreatment, indicating lesion regression. In contrast, lesions were significantly larger in mice receiving only niclosamide and pravastatin or L-4F and pravastatin (P < 0.001). In vitro niclosamide and L-4F tightly associated rendering the peptide resistant to trypsin digestion. Niclosamide itself did not inhibit trypsin activity. The combination of niclosamide with apolipoprotein mimetic peptides appears to be a promising method for oral delivery of these peptides.-Navab, M. P., Ruchala, A. J. Waring, R. I. Lehrer, S. Hama, G. Hough, M. N. Palgunachari, G. M. Anantharamaiah, and A. M. Fogelman. A novel method for oral delivery of apolipoprotein mimetic peptides synthesized from all L-amino acids. J. Lipid Res. 2009. 50: 1538-1547.