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).