Surface-mediated spontaneous emulsification of the acylated peptide, semaglutide.
Surface-mediated spontaneous emulsification of the acylated peptide, semaglutide.
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表面介导的酰化肽的自发乳化，半乳糖肽。
DOI：
10.1073/pnas.2305770121
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发表时间：
2024-01-30
影响因子：
11.1
通讯作者：
Wagner, Norman J.
中科院分区：
文献类型：
--
作者：
Li, Qi;Tangry, Vasudev;Allen, David P.;Seibert, Kevin D.;Qian, Ken K.;Wagner, Norman J.
我们确定了一种不希望的不稳定性的基本机制，称为“茴香酒”形成一类用于治疗2型糖尿病和肥胖症的治疗。在疏水性表面存在的情况下，酰化肽溶液中的自发乳化被阐明为物理化学条件和表面疏水性的函数，其特征在于汉森溶解度参数。胶体尺寸的定量预测证明使用经典的瑞利理论，而形成率减少到一个主曲线依赖于表面疏水性和搅拌速率。我们证明，胶体物理学和分子热力学提供定量预测的胶体液滴的大小和定性排名形成率，从而提高我们的理解这一类重要的治疗分子。由用脂肪酸侧链修饰的胰高血糖素样肽-1受体激动剂组成的酰化肽是2型糖尿病和肥胖症的一类重要治疗剂，但在疏水表面存在下易受不寻常的物理不稳定性的影响，即，自发乳化，在实践中也称为茴香酒形成。在这项工作中，使用光散射、小角X射线散射和圆二色性测量表征Semaglutide胶体相的物理性质，包括粒度分布、形状、二级结构、内部结构和内部组成，作为溶液理化条件的函数。经典的Rayleigh模型成功地预测了形成的胶体的存在和尺寸，该模型确定了控制其尺寸和形成的参数。胶体的形成被发现是由疏水表面催化，和形成率建模为自催化反应，使形成的主曲线的各种表面，阐明了机制。由于表面润湿性的差异，表面不同，这可以与汉森溶解度参数相关。这项工作提供了对这种不寻常的胶体现象的见解，并指导了制药工业中的肽合成过程和药物产品配方。
We identify the fundamental mechanisms of an undesired instability known as “ouzo” formation in a class of therapeutics used for treating type 2 diabetes and obesity. Spontaneous emulsification in solutions of acylated peptides in the presence of hydrophobic surfaces is elucidated as a function of physico-chemical conditions and surface hydrophobicity as characterized by Hansen solubility parameters. Quantitative prediction of the colloidal size is demonstrated using the classical Rayleigh theory, while formation rates reduce to a master curve dependent on the surface hydrophobicity and stirring rate. We demonstrate that colloidal physics and molecular thermodynamics provide quantitative predictions of the colloidal droplet size and qualitatively rank formation rates, thereby improving our understanding of this important class of therapeutic molecules. Acylated peptides composed of glucagon-like peptide-1 receptor agonists modified with a fatty acid side chain are an important class of therapeutics for type 2 diabetes and obesity but are susceptible to an unusual physical instability in the presence of hydrophobic surfaces, i.e., spontaneous emulsification, also known as ouzo formation in practice. In this work, light scattering, small-angle X-ray scattering, and circular dichroism measurements are used to characterize the physical properties of the semaglutide colloidal phase, including size distribution, shape, secondary structure, internal structure, and internal composition, as a function of solution physico-chemical conditions. The existence and size of the colloids formed are successfully predicted by a classical Rayleigh model, which identifies the parameters controlling their size and formation. Colloid formation is found to be catalyzed by hydrophobic surfaces, and formation rates are modeled as an autocatalytic reaction, enabling the formation of a master curve for various surfaces that elucidates the mechanism. Surfaces differ due to differences in surface wettability, which can be correlated with Hansen solubility parameters. This work provides insights into this unusual colloidal phenomenon and guides the peptide synthesis process and drug product formulation in the pharmaceutical industry.
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影响因子：
4.4
作者：
Scotti, A.;Liu, W.;Fernandez-Nieves, A.
通讯作者：
Fernandez-Nieves, A.
影响因子：
158.5
作者：
GUTNIAK, M;ORSKOV, C;EFENDIC, S
通讯作者：
EFENDIC, S
影响因子：
3.3
作者：
Nose, A;Hojo, M;Ueda, T
通讯作者：
Ueda, T
影响因子：
3.5
作者：
SOUROUR, S;KAMAL, MR
通讯作者：
KAMAL, MR
影响因子：
3.9
作者：
Hajiraissi, Roozbeh;Hanke, Marcel;Keller, Adrian
通讯作者：
Keller, Adrian