Protease-resistant glucagon like peptide-1 analogs with long-term anti-diabetes type 2 activity
Type 2 diabetes (also known as non-insulin-dependent diabetes, NIDDM) is increasing in prevalence worldwide. It is well accepted that NIDDM therapeutic approaches should rely on peptides because of the large interaction interface between glucagon like peptide-1 (GLP-1) and its cognate receptor. The size of the interface limits the efficacy of small molecule antagonists . Human GLP-1 is an endogenous 30 or 31 amino acid residue peptide that occurs in two forms; GLP-1(7– 36) amide and GLP-1(7–37). Both peptides have limited therapeutic utility owing to rapid degradation in the circulation by DPP IV peptidase and susceptibility to degradation by neutral endopeptidases (e.g. NEP24.11) [2,3]. As such, the drug discovery challenge is to make a stable GLP-1-like compound with a long half-life. In last decades, GLP-1 analogs have been extensively designed using mutagenesis-based side-chain replacement, but significant progress has not occurred until Extindin-4 was developed ...
KeywordsPeptide Bond Peptide Analog Ethyl Bond Oral Glucose Challenge Protease Resistance
This work was partially supported by Guangdong Key Laboratory of Biopharmacy (2006B60119) and Guangzhou Scientific and Technological Fund (2006Z3-E4152) to H. J. L and Z.D.S.