Albumin-binding domain extends half-life of glucagon-like peptide-1

• Published in: European journal of pharmacology Vol. 890; p. 173650
• Main Authors: Tan, Huanbo, Su, Wencheng, Zhang, Wenyu, Zhang, Jie, Sattler, Michael, Zou, Peijian
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05.01.2021
• Subjects: ABD035; ABDCon; Animals; Anti-Obesity Agents - chemistry; Anti-Obesity Agents - pharmacokinetics; Anti-Obesity Agents - pharmacology; Bioactivity; Blood Glucose - drug effects; Diabetes Mellitus, Type 2 - drug therapy; Eating - drug effects; Female; GA3; Glucagon-Like Peptide 1 - chemistry; Glucagon-Like Peptide 1 - pharmacokinetics; Glucagon-Like Peptide 1 - pharmacology; Glucagon-like peptide-1; Glucagon-Like Peptide-1 Receptor - agonists; Glucose Tolerance Test; Half-Life; Half-life extension; Humans; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacokinetics; Hypoglycemic Agents - pharmacology; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Protein Binding; Protein Domains; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - pharmacokinetics; Recombinant Fusion Proteins - pharmacology; Serum Albumin, Human - metabolism; GA3; Glucagon-like peptide-1; ABDCon; Bioactivity; ABD035; Half-life extension
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2020.173650

Glucagon-like peptide-1 (GLP-1) is considered to be a promising peptide for the treatment of type 2 diabetes mellitus (T2DM). However, the extremely short half-life of GLP-1 limits its clinical application. Albumin-binding domain (ABD) with high affinity for human serum albumin (HSA) has been used widely for half-life extension of therapeutic peptides and proteins. In the present study, novel GLP-1 receptor agonists were designed by genetic fusion of GLP-1 to three kinds of ABDs with different affinities for HSA: GA3, ABD035 and ABDCon. The bioactivities and half-lives of ABD-fusion GLP-1 proteins with different types and lengths of linkers were investigated in vitro and in vivo. The results demonstrated that ABD-fusion GLP-1 proteins could bind to HSA with high affinity. The blood glucose-lowering effect of GLP-1 was significantly improved and sustained by fusion to ABD. Meanwhile, the fusion proteins significantly inhibited food intake, which was beneficial for T2DM and obesity treatment. The half-life of GLP-1 was substantially extended by virtue of ABD. The in vivo results also showed that a longer linker inserted between GLP-1 and ABD resulted in a higher blood glucose-lowering effect. The fusion proteins generated by fusion of GLP-1 to GA3, ABD035 and ABDCon exhibited similar bioactivities and pharmacokinetics in vivo. These findings demonstrate that ABD-fusion GLP-1 proteins retain the bioactivities of natural GLP-1 and can be further developed for T2DM treatment and weight loss. It also indicates that the ABD-fusion strategy can be generally applicable to any peptide or protein, to improve pharmacodynamic and pharmacokinetic properties. [Display omitted] •Novel GLP-1 receptor agonist was designed by genetic fusion of GLP-1 to ABD.•Three kinds of ABDs were chosen for GLP-1 fusion; GA3, ABD035 and ABDCon.•The blood glucose lowering and food intake inhibitory effects were significantly improved.•The half-lives of ABD-fusion GLP-1 proteins were significantly prolonged.•ABD-fusion GLP-1 proteins have a potential for T2DM treatment in the future.