艾塞那肽合成

Synthesis of exenatide

目的:开发一种高效率、低成本合成艾塞那肽的方法以满足规模化生产需要。方法:以N-C延伸策略,将艾塞那肽的39个氨基酸分成13个小片段,先用液相法分别合成12个N端Fmoc保护小片段肽,用固相法合成第13个肽树脂片段,然后用固相法将12个小片段依次连接到第13个肽树脂片段上,得到艾塞那肽树脂,切割后得到艾塞那肽粗品。最后经反相色谱纯化、冷冻干燥等过程,得到艾塞那肽。结果:合成的艾塞那肽质谱表征结构正确,液相色谱显示纯度大于98%。结论:本方法提高了合成效率,减少杂质累积,降低了纯化难度,适合规模化生产。

Objective： To develop a high efficacy and cost-effective method for the synthesis of exenatide to meet the requirement of a scale production. Methods： Thirty-nine amino acids in exenatide were divided into 13 small protected peptide fragments based on N-C extension strategy, the first to 12 th fragments were synthesized by a liquid-phase method, respectively while the 13 th fragment was synthesized by a solid-phase method and then the first to 12 th fragments were in turn connected into. Fmoc-protective fragment to obtain exenatide resin, which was cleavaged to obtain crude exenatide. Finally, exenatide was obtained by reverse phase HPLC purification and lyophilization. Results： The structure of the synthesized exenatide was verified to be correct by mass spectrometry characterization and its purity was 98% by HPLC. Conclusion： The synthesis efficiency can be improved and the accumulation of impurities and the difficulty of purification can be reduced by this method, which is suitable for the large-scale production of exenatide.