Pharmacodynamic Evaluation Of Thioether-supplemented ?-helix Exenatide Derivatives

Exendin-4 is a new type 2 diabetes therapeutic drug.However,fast metabolic of exendin-4 is an obvious insufficient,rapidly catabolism and lost of activity by various proteases after entering the body.It's very inconvenient for the patients to maintain normal blood suger by twice daily injection.Thus,we can use the transitivity of ?-helix effection to improve stability of peptide's whole structure,through thioether stapling methods-locally stabilizing ?-helix structure of exendin-4.The aim of this study was to explore the half-life and physiological functions of thioether stapling exendin-4(Ex-4(1,5)).Firstly,the pharmacokinetic assay in SD rat showed that the half-life of re-synthesized polypeptide(Ex-4(1,5))is 2.4 fold of the half-life of exendin-4.Under high-glucose,treating mouse ?-cells MIN6 with drugs,we found that the re-synthesized polypeptide Ex-4(1,5)has the same function of increasing cAMP level and insulin secretion as exendin-4.The same experiment was done in B6 mice pancreatic islets,after which we found that Ex-4(1,5)has the same function of increasing insulin level as exendin-4.After we treated B6 mice with high-glucose and drugs,we found that Ex-4(1,5)and exendin-4 can increase the insulin level in plasma,and no significant difference was found between them.We tested the blood glucose after a single injection of drugs during 24 hours,during which Ex-4(1,5)could maintained normal postprandial glucose while exendin-4 decrease postprandial glucose only within 8 hours.These results showed that the re-synthesized polypeptide remained the biological activity of insulinotropic actions.The further study showed that after we treated the diabetic db/db mice with the drug for 2 months,the group treated with Ex-4(1,5)had much less body weigh gain and displayed reduced fatty liver.Moreover,the 24 hour metabolic cages experiment showed that compared with the PBS group,the diabetes mice in the Ex-4(1,5)group could reduce their food intake and raise the movement during the night,while the food intake showed no significant difference between PBS group and exendin group during the night.In summary,exendin-4 enhanced by thioether stapling ?-helix structure achieves longer half-life,which means that the stability of drug has been improved.The re-synthesized polypeptide not only has insulinotropic actions and glucose control functions,but also has a better effect on body weigh loss in diabetic mice.Thus,the improved physiological functions of newly modified exendin-4 provide a new way of reasonablely designing exendin-4,which have important value of application.