Efficient synthesis of Aib8-Arg34-GLP-1 (7–37) by liquid-phase fragment condensation,Journal of Peptide Science

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Efficient synthesis of Aib8-Arg34-GLP-1 (7–37) by liquid-phase fragment condensation
Journal of Peptide Science ( IF 1.8 ) Pub Date : 2022-01-22 , DOI: 10.1002/psc.3407
Jinhua Zhang _{1,

2} , Yuanzhen Dong _{1,

3} , Yufeng He _{1,

3} , Jinzhu Han _{1,

2} , Haifeng Hu ₁ , Jun Feng _{1,

3}

Affiliation

Glucagon-like peptide-1 (GLP-1) is a potential therapeutic agent for treating Type 2 diabetes, owing to its glucose-dependent capability to stimulate insulin secretion. Semaglutide is currently the best GLP-1 analogue; however, the Aib⁸-Arg³⁴-GLP-1 (7–37) of semaglutide contains an unnatural amino acid at the eighth position (Aib: 2-aminoisobutyric acid), which hinders its fermentation process. Aib⁸-Arg³⁴-GLP-1 (7–37) is mainly synthesised by solid-phase synthesis. However, solid-phase synthesis of Aib⁸-Arg³⁴-GLP-1 (7–37) has many shortcomings: (i) The synthesis requires many organic solvents, (ii) the existence of deletion peptides impedes the subsequent purification process, (iii) the yield is low (approximately 16%), and (iv) it is not suitable for large-scale synthesis. However, the synthesis of Aib⁸-Arg³⁴-GLP-1 (7–37) by liquid-phase fragment condensation of expressed and synthetic peptides (Arg³⁴-GLP-1 (9–37) and Boc-His (Boc)-Aib) has many advantages: (i) The synthesis process only requires a few organic reagents, (ii) the yield is high (approximately 60%), (iii) the purification conditions are simple and Aib⁸-Arg³⁴-GLP-1 (7–37) with a purity of over 98% is obtained through one-step reverse-phase purification, and (iv) the raw materials are inexpensive and large-scale synthesis is possible. In conclusion, here, we developed an efficient method for synthesising Aib⁸-Arg³⁴-GLP-1 (7–37).

中文翻译：

通过液相片段浓缩高效合成 Aib8-Arg34-GLP-1 (7-37)

胰高血糖素样肽-1 (GLP-1) 是治疗 2 型糖尿病的潜在治疗剂，因为它具有刺激胰岛素分泌的葡萄糖依赖性能力。索马鲁肽是目前最好的 GLP-1 类似物；然而，semaglutide 的 Aib ⁸ -Arg ³⁴ -GLP-1 (7-37) 在第八位含有非天然氨基酸（Aib：2-氨基异丁酸），这阻碍了其发酵过程。Aib ⁸ -Arg ³⁴ -GLP-1 (7-37) 主要通过固相合成来合成。^{然而，Aib 8} -Arg ³⁴的固相合成-GLP-1（7-37）有很多缺点：（i）合成需要很多有机溶剂，（ii）缺失肽的存在阻碍了后续的纯化过程，（iii）收率低（约16%）， (iv) 不适合大规模合成。然而，Aib ⁸ -Arg ³⁴ -GLP-1 (7-37) 通过表达和合成肽（Arg ³⁴ -GLP-1 (9-37) 和 Boc-His (Boc)- Aib)有很多优点：(i)合成过程只需要很少的有机试剂，(ii)收率高(约60%)，(iii)纯化条件简单，Aib ⁸ -Arg ³⁴-GLP-1(7-37)通过一步反相纯化获得纯度98%以上，(iv)原料便宜，可大规模合成。总之，在这里，我们开发了一种合成 Aib ⁸ -Arg ³⁴ -GLP-1 (7-37) 的有效方法。

更新日期：2022-01-22

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