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首页> 外文期刊>Journal of Pharmacy and Pharmacology >Poly(L-lysine) as a model drug macromolecule with which to investigate secondary structure and membrane transport, part I: Physicochemical and stability studies.
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Poly(L-lysine) as a model drug macromolecule with which to investigate secondary structure and membrane transport, part I: Physicochemical and stability studies.

机译：聚（L-赖氨酸）作为模型药物大分子，用于研究二级结构和膜运输，第一部分：理化和稳定性研究。

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Low oral bioavailability of therapeutic peptides and proteins generally results from their poor permeability through biological membranes and enzymatic degradation in the gastrointestinal tract. Since different secondary structures exhibit different physicochemical properties such as hydrophobicity, size and shape, changing the secondary structure of a therapeutic polypeptide may be another approach to increasing its membrane permeation. Poly(L-lysine) was used as a model polypeptide. The objectives of this study were to induce secondary structural changes in poly(L-lysine) and to determine the time course over which a given conformer was retained. In addition, the hydrophobicity of each secondary structure of poly(L-lysine) was assessed. The circular dichroism (CD) studies demonstrated that the conditions employed could successfully induce the desired secondary structural changes in poly(L-lysine). The alpha-helix conformer appeared to be more stable at 25 degrees C whereas the beta-sheet conformer could be preserved at 37 degrees C. On the other hand, the random coil conformer was retained at both temperatures. Significant losses of the alpha-helix and the beta-sheet conformers were observed when the pH was reduced. The change in ionic strength did not affect any of the conformers. The octanol/buffer partitioning studies indicated that the alpha-helix and the beta-sheet conformers exhibited significantly different (P < 0.05) hydrophobicities. In conclusion, variation of pH and temperature conditions can be used to induce secondary structural changes in poly(L-lysine). These changes are reversible when the stimuli are removed. The alpha-helix and the beta-sheet conformers of poly(L-lysine) are more lipophilic than the native random coil conformer. Thus, poly(L-lysine) may represent an ideal model polypeptide with which to further investigate the effects of secondary structure on membrane diffusion or permeation.
机译：治疗性肽和蛋白质的口服生物利用度低通常是由于它们通过生物膜的渗透性差以及在胃肠道中的酶促降解。由于不同的二级结构表现出不同的理化性质，例如疏水性，大小和形状，因此改变治疗性多肽的二级结构可能是增加其膜渗透性的另一种方法。聚（L-赖氨酸）用作模型多肽。这项研究的目的是诱导聚（L-赖氨酸）的二级结构变化，并确定保留给定构象异构体的时间过程。另外，评估了聚（L-赖氨酸）的每个二级结构的疏水性。圆二色性（CD）研究表明所采用的条件可以成功地诱导聚（L-赖氨酸）中所需的二级结构变化。 α-螺旋构象异构体似乎在25°C时更稳定，而β-sheet构象异构体可以在37°C保存。另一方面，无规卷曲构象异构体在两种温度下均保持不变。当pH降低时，观察到α-螺旋和β-折叠构象异构体的显着损失。离子强度的变化不影响任何构象异构体。辛醇/缓冲液分配研究表明，α-螺旋和β-折叠构象异构体表现出明显不同的疏水性（P <0.05）。总之，pH和温度条件的变化可用于诱导聚L-赖氨酸的二级结构变化。去除刺激后，这些变化是可逆的。聚（L-赖氨酸）的α-螺旋和β-折叠构象比天然无规卷曲构象更亲脂。因此，聚（L-赖氨酸）可以代表一种理想的模型多肽，用它可以进一步研究二级结构对膜扩散或渗透的影响。

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