A comprehensive study on the identification and characterization of major degradation products of synthetic liraglutide using liquid chromatography-high resolution mass spectrometry.

IF 1.8 4区生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Peptide Science Pub Date : 2024-08-20 DOI:10.1002/psc.3652

Devendra Badgujar, Sanket Bawake, Nitish Sharma

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引用次数: 0

Abstract

Liraglutide (LGT) is a synthetic glucagon-like peptide-1 analogue mainly used for the treatment of type-2 diabetes or obesity. Comprehensive stability testing is essential in the development and routine quality control of synthetic therapeutic peptide pharmaceuticals. The GLP-1 peptide drugs are usually formulated in aqueous-base solution, which can generate stability issues during manufacturing, storage or shipment. The current study endeavors to observe the chemical stability behavior of LGT by exposing the drug substance to oxidative and hydrolytic stress conditions. A simple liquid chromatography (LC) method was developed where sufficient resolution between LGT and the generated degradation products was achieved. In total, 19 degradation products (DPs) were separated under acidic, basic and oxidative stress conditions. Using LC-HRMS, MS/MS studies, the generated degradation products were identified and characterized. The mechanistic fragmentation pathway for all generated DPs were established and the plausible chemical structure for the identified DPs was predicted based on MS/MS data. The results strongly suggest that LGT is highly susceptible to degrade under oxidative and hydrolytic conditions. Furthermore, this study provides insights into the hydrolytic and oxidative stability of LGT, which can be implied during generic and novel formulation drug development and discovery in synthesizing relatively stable GLP-1 analogues.

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利用液相色谱-高分辨质谱法对合成利拉鲁肽的主要降解产物进行鉴定和表征的综合研究。

利拉鲁肽（LGT）是一种合成的胰高血糖素样肽-1 类似物，主要用于治疗 2 型糖尿病或肥胖症。全面的稳定性测试对于合成治疗肽类药物的开发和日常质量控制至关重要。GLP-1 肽药物通常配制成水基溶液，在生产、储存或运输过程中会产生稳定性问题。本研究试图通过将药物物质置于氧化和水解应力条件下，观察 LGT 的化学稳定性。研究人员开发了一种简单的液相色谱（LC）方法，该方法在 LGT 和生成的降解产物之间实现了足够的分辨率。在酸性、碱性和氧化应激条件下，共分离出 19 种降解产物（DPs）。通过 LC-HRMS 和 MS/MS 研究，对生成的降解产物进行了鉴定和表征。根据 MS/MS 数据，确定了所有产生的降解产物的机理碎片途径，并预测了已确定的降解产物的合理化学结构。研究结果表明，LGT 极易在氧化和水解条件下降解。此外，本研究还深入揭示了 LGT 的水解和氧化稳定性，这将有助于普通制剂和新型制剂药物的开发和发现，从而合成相对稳定的 GLP-1 类似物。

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来源期刊

Journal of Peptide Science 生物-分析化学

CiteScore

3.40

自引率

4.80%

发文量

审稿时长

1.7 months

期刊介绍： The official Journal of the European Peptide Society EPS The Journal of Peptide Science is a cooperative venture of John Wiley & Sons, Ltd and the European Peptide Society, undertaken for the advancement of international peptide science by the publication of original research results and reviews. The Journal of Peptide Science publishes three types of articles: Research Articles, Rapid Communications and Reviews. The scope of the Journal embraces the whole range of peptide chemistry and biology: the isolation, characterisation, synthesis properties (chemical, physical, conformational, pharmacological, endocrine and immunological) and applications of natural peptides; studies of their analogues, including peptidomimetics; peptide antibiotics and other peptide-derived complex natural products; peptide and peptide-related drug design and development; peptide materials and nanomaterials science; combinatorial peptide research; the chemical synthesis of proteins; and methodological advances in all these areas. The spectrum of interests is well illustrated by the published proceedings of the regular international Symposia of the European, American, Japanese, Australian, Chinese and Indian Peptide Societies.