Design And Synthesis Of Hapeten-Exenatide Conjugate

Diabetes treatment drugs have always been one of the research hotspots.GLP-1 receptor agonists are considered to be the most important diabetes treatments in the future.However,since native GLP-1 has only a very limited plasma half-life of a few minutes before degradation.Therefore,the current research focus on how to prolong the half-life of the drug more than improve the drug efficacy.Long-acting GLP-1 receptor agonists can reduce the frequency of administration by subcutaneous injection to improve the quality of life of patients.And studies have shown that long-acting GLP-1 has a very large advantage over short-acting drugs.In this paper,the GLP-1 structural analog exenatide was used as the research object.Refer to the previous outstanding results of prolonging the half-life of GLP-1 receptor agonists.A method by which extending half-life of somaglutide in human body by conjugating fatty acids can be used in this study.In this paper,we designed a C-terminal modified exenatide with antibodies to recruit small molecules 2,4-dinitrobenzene and rhamnose to achieve the purpose of prolonging the half-life of exenatide.To achieve this,a small molecule analog was recruited using antibodies to the Exetinide and GGG sequences,respectively,modified with the LPETGG sequence using a Sortase A-mediated enzyme ligation method.The effect of the length of the connecting arm on the drug activity was also investigated.The exenatide analog and the six antibody recruitment small molecules were obtained by chemical synthesis.The Sortase A enzyme reaction indicated that the method of designing the linkage was fast and efficient.And the enzymatic reactions of the three 2,4-dinitrobenzene analogs were slightly better than the three rhamnose analogs.The length of the linker will significantly affect the rate of enzyme reaction,and the longer the linker reacts,the slower it will be.At the same time,the small molecule containing the longest connecting arm in rhamnose was incompletely reacted,and this situation only showed a slowing of the reaction in 2,4-dinitrobenzene.Finally,the yield of each target molecule was about 50%.Subsequent preliminary cell activity experiments showed that the modification of 2,4-dinitrobenzene and rhamnose did not seriously affect the activity of exenatide.Experiments have demonstrated the feasibility of recruiting small molecules by Sortase A at the C-terminal modification of Exenatide,And provide reference for the design and development of future peptide drugs.