Mol Pharm. 2019 May 6;16(5):2153-2161. doi: 10.1021/acs.molpharmaceut.9b00106. Epub 2019 Apr 25.
Peptides and proteins commonly have complex structural landscapes allowing for transformation into a wide array of species including oligomers, aggregates, and fibrils. The formation of undesirable forms including aggregates and fibrils poses serious risks from the perspective of drug development and disease. Liraglutide, a GLP-1 agonist for the treatment of diabetes, is a conjugated peptide that forms oligomers that can be stabilized by pH and organic solvents. We have developed an analytical toolkit to overcome challenges inherent to Liraglutide's conjugated acyl chain and probed the impact its oligomers have on its physical stability. Our studies show that Liraglutide's oligomer states have significant and potentially detrimental impacts on its propensity to aggregate and form fibrils as well as its potency. Liraglutide delivered as a synthetic peptide is able to maintain its oligomerization state in dried lyophilized powders, acting as a memory effect from its synthetic process and purification. Through Liraglutide's oligomer memory effect, we demonstrate the importance and impact the process for synthetic peptides can have on drug development spanning from discovery to formulation development.
肽和蛋白质通常具有复杂的结构景观，允许它们转化为多种形式，包括低聚物、聚集体和纤维。从药物开发和疾病的角度来看，包括聚集体和纤维在内的不理想形式的形成带来了严重的风险。利拉鲁肽是一种用于治疗糖尿病的 GLP-1 激动剂，它是一种缀合肽，可形成低聚物，这些低聚物可通过 pH 值和有机溶剂稳定。我们开发了一个分析工具包来克服利拉鲁肽共轭酰链所固有的挑战，并研究了其低聚物对其物理稳定性的影响。我们的研究表明，利拉鲁肽的低聚物状态对其聚集和形成纤维的倾向以及其效力有重大的潜在不利影响。作为合成肽给予的利拉鲁肽能够在干燥的冻干粉末中保持其低聚状态，这是其合成过程和纯化的记忆效应。通过利拉鲁肽的低聚物记忆效应，我们证明了合成肽的过程在从发现到制剂开发的药物开发中具有重要性和影响。
