The Effect of Lipidation on the Self-Assembly of the Gut-Derived Peptide Hormone PYY3–36,Bioconjugate Chemistry

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The Effect of Lipidation on the Self-Assembly of the Gut-Derived Peptide Hormone PYY3–36
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2018-06-01 00:00:00 , DOI: 10.1021/acs.bioconjchem.8b00286
Jessica A. Hutchinson ₁ , Samuel Burholt ₁ , Ian W. Hamley ₁ , Anna-Karin Lundback ₂ , Shahid Uddin ₂ , Ana Gomes dos Santos ₂ , Mehedi Reza ₃ , Jani Seitsonen ₃ , Janne Ruokolainen ₃

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Lipidation is a powerful strategy to improve the stability in vivo of peptide drugs. Attachment of a lipid chain to a hydrophilic peptide leads to amphiphilicity and the potential for surfactant-like self-assembly. Here, the self-assembly and conformation of three lipidated derivatives of the gastrointestinal peptide hormone PYY_3–36 is examined using a comprehensive range of spectroscopic, scattering, and electron microscopy methods and compared to those of the parent PYY_3–36 peptide. The peptides are lipidated at Ser(11), Arg(17), or Arg(23) in the peptide; the former is within the β-turn domain (based on the published solution NMR structure), and the latter two are both within the α-helical domain. We show that it is possible to access a remarkable diversity of nanostructures ranging from micelles to nanotapes and fibrillar hydrogels by control of assembly conditions (concentration, pH, and temperature). All of the lipopeptides self-assemble above a critical aggregation concentration (cac), determined through pyrene fluorescence probe measurements, and they all have predominantly α-helical secondary structure at their native pH. The pH and temperature dependence of the α-helical conformation were probed via circular dichroism spectroscopy experiments. Lipidation was found to provide enhanced stability against changes in temperature and pH. The self-assembled structures were investigated using small-angle X-ray scattering (SAXS) and cryogenic transmission electron microscopy (cryo-TEM). Distinct differences in nanostructure were observed for lipidated and unlipidated peptides, also depending on the position of lipidation. Remarkably, micelles containing lipopeptides with α-helical peptide conformation were observed. Gelation was observed at higher concentrations in certain pH intervals for the lipidated peptides, but not for unlipidated PYY_3–36. Thus, lipidation, in addition to enhancing stability against pH and temperature variation, also provides a route to prepare PYY peptide hydrogels. These findings provide important insights into the control of PYY_3–36 conformation and aggregation by lipidation, relevant to the development of future therapeutics based on this peptide hormone, for example, in treatments for obesity.

中文翻译：

脂化对肠道衍生肽激素PYY _3–36自组装的影响

脂质化是提高肽药物体内稳定性的有效策略。脂质链与亲水性肽的连接会导致两亲性，并可能产生类似表面活性剂的自组装。在这里，使用一系列光谱，散射和电子显微镜方法检查了胃肠肽激素PYY _3–36的三种脂化衍生物的自组装和构象，并将其与母体PYY _{3–36进行了比较。}肽。肽在肽的Ser（11），Arg（17）或Arg（23）处脂化；前者在β-turn域内（基于已发布的溶液NMR结构），而后两者均在α-螺旋域内。我们表明，可以通过控制组装条件（浓度，pH和温度）来访问从胶束到纳米带和原纤维水凝胶的大量纳米结构。通过pyr荧光探针测量确定，所有脂肽都在临界聚集浓度（cac）以上自组装，它们在其天然pH值上均主要具有α-螺旋二级结构。通过圆二色光谱实验探究了α-螺旋构象的pH和温度依赖性。发现脂质作用提供了针对温度和pH变化的增强的稳定性。使用小角度X射线散射（SAXS）和低温透射电子显微镜（cryo-TEM）研究了自组装结构。脂化和未脂化的肽在纳米结构上观察到不同的差异，这也取决于脂化的位置。明显地，观察到含有具有α-螺旋肽构象的脂肽的胶束。在一定的pH间隔内，脂化肽在较高浓度下观察到凝胶化，而未脂化的PYY没有观察到胶凝脂化和未脂化的肽在纳米结构上观察到不同的差异，这也取决于脂化的位置。明显地，观察到含有具有α-螺旋肽构象的脂肽的胶束。在一定的pH间隔内，脂化肽在较高浓度下观察到凝胶化，而未脂化的PYY没有观察到胶凝脂化和未脂化的肽在纳米结构上观察到不同的差异，这也取决于脂化的位置。明显地，观察到含有具有α-螺旋肽构象的脂肽的胶束。在一定的pH间隔内，脂化肽在较高浓度下观察到凝胶化，而未脂化的PYY没有观察到胶凝_3–36。因此，脂质化除了增强针对pH和温度变化的稳定性之外，还提供了制备PYY肽水凝胶的途径。这些发现为通过脂化控制PYY _3–36构象和聚集提供了重要的见识，这与基于这种肽激素的未来疗法的开发有关，例如在肥胖症治疗中。

更新日期：2018-06-01

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