Wang Ying, Lomakin Aleksey, Kanai Sonoko, Alex Rainer, Benedek George B
Materials Processing Center, ‡Department of Physics, and §Center for Materials Science and Engineering, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
Mol Pharm. 2015 Feb 2;12(2):411-9. doi: 10.1021/mp500519s. Epub 2015 Jan 20.
Oligomerization of lipidated peptides is of general scientific interest and is important in biomedical and pharmaceutical applications. We investigated the solution properties of a lipidated peptide, Liraglutide, which is one of the glucagon-like peptide-1 (GLP-1) agonists used for the treatment of type II diabetes. Liraglutide can serve as a model system for studying biophysical and biochemical properties of micelle-like self-assemblies of the lipidated peptides. Here, we report a transformation induced in Liraglutide oligomers by changing pH in the vicinity of pH 7. This fully reversible transformation is characterized by changes in the size and aggregation number of the oligomer and an associated change in the secondary structure of the constituent peptides. This transformation has quite slow kinetics: the equilibrium is reached in a course of several days. Interestingly, while the transformation is induced by changing pH, its kinetics is essentially independent of the final pH. We interpreted these findings using a model in which desorption of the monomer from the oligomer is the rate-limiting step in the transformation, and we determined the rate constant of the monomer desorption.
脂化肽的寡聚化具有普遍的科学意义，在生物医学和制药应用中也很重要。我们研究了一种脂化肽——利拉鲁肽的溶液性质，它是用于治疗II型糖尿病的胰高血糖素样肽-1（GLP-1）激动剂之一。利拉鲁肽可以作为研究脂化肽类胶束状自组装体生物物理和生化性质的模型系统。在此，我们报道了通过在pH 7附近改变pH值在利拉鲁肽寡聚体中诱导的一种转变。这种完全可逆的转变的特征是寡聚体的大小和聚集数发生变化，以及组成肽的二级结构发生相关变化。这种转变具有相当缓慢的动力学：平衡在几天内达到。有趣的是，虽然转变是由改变pH值诱导的，但其动力学基本上与最终pH值无关。我们使用一个模型来解释这些发现，在该模型中，单体从寡聚体上的解吸是转变中的限速步骤，并且我们确定了单体解吸的速率常数。
