Exendin-4 derivative and solid phase chemical synthesis thereof

Abstract

The invention discloses an Exendin-4 derivant with Exendin-4 activity and preparation and application thereof, belonging to the technical field of biological engineering. The molecular structural formula of the derivant is any one of the following structures: Exendin-4(1-39)-Xaa40(Seq ID No.2), Exendin-4(1-39)-Xaa40-Xaa41(Seq ID No.3), Exendin-4 (1-39)-Xaa40-Xaa41-Xaa42(Seq ID No.4), Exendin-4(1-30)-Xaa31(Seq ID No.6), Exendin-4(1-30)-Xaa31-Xaa32(Seq ID No.7) and / or Exendin-4 (1-30)-Xaa31-Xaa32-Xaa33(Seq ID No.8); wherein, Xaa40, Xaa41, Xaa42, Xaa31, Xaa32 and Xaa33 are respectively any amino acid of Cys, Ala, Gly, His, Ser and Thr. The Exendin-4 derivant has the advantage that the derivant has longer in-vivo drug effect time than Exendin-4. Solid phase chemosynthesis is adopted to prepare the Exendin-4 derivant, so that production steps are few and production cost is low. The Exendin-4 derivant is particularly suitable for preparing the active ingredient of drugs for curing diabetes.

Description

technical field [0001] The invention relates to an Exendin-4 derivative with Exendin-4 activity and its solid-phase chemical synthesis, belonging to the technical field of bioengineering. Background technique [0002] Diabetes is one of the three major diseases that threaten human health. The incidence rate is extremely high, and it is increasing year by year. Its obvious clinical symptoms are that the glucose content in blood and urine exceeds the normal range, accompanied by "three more and one less", that is, eating more, Polydipsia, polyuria and weight loss. Among them, type II diabetes patients account for more than 90%. For a long time, people have mainly used drugs such as sulfonylureas and biguanides to treat type II diabetes, but these drugs have relatively large side effects, and long-term use can lead to pancreatic β-cell failure. A glucagon-like peptide 1 (GLP-1) secreted by the human body can stimulate insulin secretion when blood sugar is high, thereby lowerin...

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Problems solved by technology

However, GLP-1 will be rapidly degraded and inactivated by dipeptidyl peptidase IV (DPPIV) in vivo, and its half-life is less than 2 minutes, so its clinical application is limited.

[0006] Studies have shown that the C-terminal 9 peptide of Exendin-4 plays an important role in its activity, so the above-mentioned truncated Exendin-4 will have different degrees of decline in activity compared with the original peptide; although the method of changing the amino acid species in the peptide chain is beneficial Production, but the effect of improving stability and prolonging the drug effect time in vivo is not significant, such as: the Exendin-4 analog obtained by replacing Met with Leu at the 14th position and Trp with Phe at the 25th position and Exendin -4 Compared with the in vivo drug effect time, it is not prolonged; the preparation process of Exendin derivatives modified with polyethylene glycol is more complicated, the product separation and purification are difficult, and the yield is very low, which is not conducive to industrial production

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