Efficient synthesis of Aib8‐Arg34‐GLP‐1 (7–37) by liquid‐phase fragment condensation

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).