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Tan, H.* ; Su, W.* ; Zhang, W.* ; Zhang, J.* ; Sattler, M. ; Zou, P.

Generation of novel long-acting GLP-1R agonists using DARPins as a scaffold.

Int. J. Pharm. 607:121043 (2021)
Open Access Green as soon as Postprint is submitted to ZB.
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, Issue: , Pages: , Article Number: 121043 Supplement: ,
Publisher Elsevier
Publishing Place Amsterdam
Reviewing status Peer reviewed
Grants Youth Innovation Promotion Association, Chinese Academy of Sciences
National Natural Science Foundation of China