Synthesis And Hypoglycemic Activity Of Semaglutide Analogues

Semaglutide is a long-acting glucagon-like peptide-1?GLP-1?analogue developed by Novo Nordisk Biotechnology Co.,Ltd.Denmark,which has excellent,safe and reliable hypoglycemic effect.At the same time,it also plays a good role in weight loss and cardiovascular system benefits.Its huge market value and academic value have attracted the research and development interest of many domestic and foreign giant pharmaceutical companies and scientific research institutions.At present,the main preparation methods of semaglutide include biological fermentation and solid-phase synthesis,in which the impurities produced by biological fermentation can easily to cause immunogenicity,etc.,which affect the biological activity of peptide drugs,and the scale of production is not easy to be enlarged.However,the solid phase method has a late start and the technology is relatively immature.Therefore,it is of great significance to develop a new synthetic method for semaglutide to provide a reference for the solid phase synthesis of peptide drugs.In this dissertation,a variety of new synthesis methods were designed after sufficient literature research.A method for synthesizing semalutide and its analogues was developed with better synthetic efficiency by screening synthetic methods and optimizing reaction conditions.A series of semaglutide analogues Mp1-Mp18including deletion peptides,racemic peptides,insertion peptides,hydrolysates,replacement peptides,and reducing peptides were prepared,which were confirmed by time-of-flight mass spectrometry and peptide sequence tests.HEK293 cells with high expression of glucagon-like peptide-1 receptor?GLP-1R?were constructed by transfection technique,and GLP-1R agonists were used to act on HEK293 cells with high expression of GLP-1R.The content of c AMP stimulated by the compound was measured to evaluate the agonistic activity of Mp1-Mp18.The results showed that in the structure-activity of the semaglutide analogue,the deletion peptide of Gly³⁷,the hydrolysate of Gln²³,and the insertion peptide of Gly³⁵ showed a certain hypoglycemic activity,and the isomer of Arg³⁶ showed a better hypoglycemic activity(EC₅₀0.01663±0.00312n M)than Semaglutide.