Semaglutide is currently the most promising antidiabetic drug, especially for the treatment of type 2 diabetes mellitus, due to its excellent efficacy in glycemic control and weight loss. However, the production of semaglutide remains high cost, and high yield, low cost, and high purity still remains a challenge. Herein, we reported a convenient and high-yield strategy for the preparation of semaglutide through fragmented condensation coupling, involving solid-phase peptide synthesis of tetrapeptide and on-column refolding and on-column enzyme cleavage based inclusion body expression of LysArgGLP-1 (11–37) with fused protein tags in an X-Y-D4K-G pattern. The optimized N-terminal protein tag significantly boosts inclusion body expression level, while on-column refolding and on-column enzyme cleavage avoid precipitation, enhancing efficiency and yield together with one-step purification. The successful preparation of semaglutide is expected to achieve large-scale industrial production with low cost, high yield and high purity.

中文翻译：

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固相合成和包涵体表达两步法制备索马鲁肽


索马鲁肽是目前最有前途的抗糖尿病药物，尤其是治疗2型糖尿病，因其在血糖控制和减肥方面具有优异的功效。然而，索马鲁肽的生产成本仍然较高，高产率、低成本、高纯度仍然是一个挑战。在此，我们报道了一种通过片段化缩合偶联制备索马鲁肽的便捷高产策略，包括四肽的固相肽合成以及基于柱上重折叠和柱上酶裂解的 LysArgGLP-1 包涵体表达（11 –37) 带有 XY-D4K-G 模式的融合蛋白标签。优化的N端蛋白标签显着提高了包涵体表达水平，同时柱上复性和柱上酶切避免了沉淀，提高了效率和产量以及一步纯化。索马鲁肽的成功制备有望实现低成本、高收率、高纯度的大规模工业化生产。