Dept. of Chemical Science and Technologies, University of Rome Tor Vergata, Via Ricerca Scientifica, 1, 00133 Rome, Italy.
Soft Matter. 2020 Nov 18;16(44):10122-10131. doi: 10.1039/d0sm01011a.
The aggregation properties of semaglutide, a lipidated peptide drug agonist of the Glucagon-like peptide 1 receptor recently approved for the treatment of type 2 diabetes, have been investigated by spectroscopic techniques (UV-Vis absorption, steady-state and time-resolved fluorescence, and electronic circular dichroism) and molecular dynamics simulations. We show that in the micromolar concentration region, in aqueous solution, semaglutide is present as monomeric and dimeric species, with a characteristic monomer-to-dimer transition occurring at around 20 μM. The lipid chain stabilizes a globular morphology of the monomer and dimer species, giving rise to a locally well-defined polar outer surface where the lipid and peptide portions are packed to each other. At very long times, these peptide clusters nucleate the growth of larger aggregates characterized by blue luminescence and a β-sheet arrangement of the peptide chains. The understanding of the oligomerization and aggregation potential of peptide candidates is key for the development of long acting and stable drugs.
最近被批准用于治疗 2 型糖尿病的胰高血糖素样肽 1 受体的脂肪肽激动剂司美格鲁肽的聚集性质已通过光谱技术（紫外-可见吸收、稳态和时间分辨荧光以及电子圆二色性）和分子动力学模拟进行了研究。我们表明，在微摩尔浓度区域中，在水溶液中，司美格鲁肽以单体和二聚体形式存在，在大约 20 μM 处发生特征性的单体到二聚体的转变。脂质链稳定了单体和二聚体的球形形态，形成了局部定义良好的极性外表面，其中脂质和肽部分彼此堆积。在很长的时间内，这些肽簇可以引发具有蓝色荧光和肽链β-折叠排列的更大聚集体的生长。了解肽候选物的低聚和聚集潜力对于开发长效和稳定的药物至关重要。
