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Open Access Green as soon as Postprint is submitted to ZB.
Generation of novel long-acting GLP-1R agonists using DARPins as a scaffold.
Int. J. Pharm. 607:121043 (2021)
Glucagon-like peptide-1 (GLP-1) has been considered to be a promising peptide for treatment of type 2 diabetes mellitus (T2DM). However, the extremely short half-life (minutes) of native GLP-1 limits its clinical application potential. Here, we designed two GLP-1 analogues by genetic fusion of GLP-1 to one or two tandem human serum albumin-binding designed ankyrin repeat proteins (DARPins), denoted as GLP-DARPin or GLP-2DARPin. The two DARPin-fusion GLP-1 proteins were expressed in E. coli and purified, followed by measurements of their bioactivities and half-lives in mice. The results revealed that the half-life of GLP-2DARPin, binding two HSA molecules, was approximately 3-fold longer than GLP-DARPin (52.3 h versus 18.0 h). In contrast, the bioactivity results demonstrated that the blood glucose-lowering effect of GLP-DARPin was more potent than that of GLP-2DARPin. The oral glucose tolerance tests indicated that blood glucose levels were significantly reduced for at least 48 hours by GLP-DARPin, but were reduced for only 24 h by GLP-2DARPin. Injected once every two days, GLP-DARPin substantially reduced blood glucose levels in streptozotocin (STZ)-induced diabetic mice to the same levels as normal mice. During the treatment course, GLP-DARPin significantly reduced the food intake and body weight of diabetic mice up to approximately 17% compared with the control group. A histological analysis revealed that GLP-DARPin alleviated islet loss in diabetic mice. These findings suggest that long-acting GLP-DARPin holds great potential for further development into drugs for the treatment of T2DM and obesity. Meanwhile, our data indicate that albumin-binding DARPins can be used as a universal scaffold to improve the pharmacokinetic profiles and pharmacological activities of therapeutic peptides and proteins.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Glucagon-like Peptide-1 ; Bioactivity ; Designed Ankyrin Repeat Proteins ; Genetic Fusion ; Half-life; Glucagon-like Peptide-1; Albumin-binding Domain; Half-life Extension; Receptor Agonists; In-vitro; Fusion; Affinity; Protein; Antibodies; Discovery
ISSN (print) / ISBN
0378-5173
e-ISSN
1873-3476
Quellenangaben
Volume: 607,
Article Number: 121043
Publisher
Elsevier
Publishing Place
Amsterdam
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Structural Biology (STB)
Grants
Youth Innovation Promotion Association, Chinese Academy of Sciences
National Natural Science Foundation of China
National Natural Science Foundation of China