Development of a pharmacologically improved peptide agonist of the leptin receptor
Development of a pharmacologically improved peptide agonist of the leptin receptor
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DOI：
10.1016/j.bbamcr.2008.05.007
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发表时间：
2008-10-01
影响因子：
5.1
通讯作者：
Surmacz, Eva
中科院分区：
文献类型：
--
作者：
Otvos, Laszlo, Jr.;Terrasi, Marianna;Surmacz, Eva
瘦素是一种由脂肪组织产生的激素，调节下丘脑的能量平衡，与不孕、免疫反应和癌变有关。与瘦素缺乏和瘦素过剩相关的疾病的存在要求开发激活或抑制瘦素受体（ObR）的药物。我们合成了四个拟议的受体结合瘦素片段（位点I， IIa和IIb， III），它们的拮抗剂类似物，以及由两个不连续的位点II臂组成的肽嵌合体。为了评估瘦素片段的药理效用，我们研究了肽刺激obr阳性和obr阴性细胞生长的能力。结合II位点构建物和III位点衍生物，在中等纳摩尔浓度下选择性逆转瘦素诱导的obr阳性细胞的生长。然而，这些肽似乎是部分激动剂/拮抗剂，因为它们在缺乏外源性瘦素的情况下激活细胞生长。一种设计位点III类似物，在末端位置具有非天然氨基酸以减少蛋白质水解和增强血脑屏障（BBB）渗透的碳水化合物部分，被证明是ObR的完全激动剂，即在存在或不存在瘦素的情况下，刺激不同的ObR阳性细胞的增殖，而不是ObR阴性细胞。在固相实验中，该糖肽与分离的ObR结合，并在100-500 nM浓度下激活ObR阳性MCF-7细胞中的ERK-1/2信号传导。糖肽在小鼠血清中稳定，在细胞性血脑屏障模型中容易穿过内皮/星形胶质细胞层，并在腹腔给药后分布到Balb/c小鼠脑内。这些特征表明设计位点III糖肽在瘦素缺乏疾病中具有潜在的药物效用。(c) 2008 Elsevier B.V.版权所有
Leptin, a hormone produced by adipose tissue, regulates energy balance in the hypothalamus and is involved infertility, immune response and carcinogenesis. The existence of disorders related to leptin deficit and leptin overabundance calls for the development of drugs activating or inhibiting the leptin receptor (ObR). We synthesized four proposed receptor-binding leptin fragments (sites I, IIa and IIb, III), their reportedly antagonist analogs, and a peptide chimera composed of the two discontinuous site II arms. To assess the pharmacological utility of leptin fragments, we studied the peptides' ability to stimulate the growth of ObR-positive and ObR-negative cells. The combined site II construct and site III derivatives selectively reversed leptin-induced growth of ObR-positive cells at mid-nanomolar concentrations. However, these peptides appeared to be partial agonists/antagonists as they activated cell growth in the absence of exogenous leptin. A designer site III analog, featuring non-natural amino acids at terminal positions to decrease proteolysis and a blood-brain barrier (BBB) penetration-enhancing carbohydrate moiety, proved to be full agonist to ObR, i.e., stimulated proliferation of different ObR-positive but not ObR-negative cells in the presence or absence of leptin. This glycopeptide bound to isolated ObR on solid-phase assays and activated ERK-1/2 signaling in ObR-positive MCF-7 cells at 100-500 nM concentrations. The glycopeptide was stable in mouse serum, readily crossed endothelial/astrocyte cell layers in a cellular BBB model, and was distributed into the brain of Balb/c mice after intraperitoneal administration. These characteristics suggest a potential pharmaceutical utility of the designer site III glycopeptide in leptin-deficient diseases. (c) 2008 Elsevier B.V. All rights reserved.