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

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

Eur. J. Pharmacol. 890:173650 (2021)
Postprint DOI
Open Access Green
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Abd035 ; Abdcon ; Bioactivity ; Ga3 ; Glucagon-like Peptide-1 ; Half-life Extension; Antibody Fusion Protein; Single-chain Diabody; Affinity; Liraglutide; Expression; Platform; Linkers; Obesity; Design; Glp-1
ISSN (print) / ISBN 0014-2999
e-ISSN 0014-2999
Zeitschrift European Journal of Pharmacology
Quellenangaben Band: 890, Heft: , Seiten: , Artikelnummer: 173650 Supplement: ,
Verlag Elsevier
Verlagsort Radarweg 29, 1043 Nx Amsterdam, Netherlands
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Structural Biology (STB)
Förderungen Youth Innovation Promotion Association, Chinese Academy of Sciences
National Natural Science Foundation of China