Long-acting agonists of human and rodent GLP-2 receptors for studies of the physiology and pharmacological potential of the GLP-2 system

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Background and Purpose: Glucagon-like peptide-2 (GLP-2) is secreted postprandially from enteroendocrine Lcells and has anabolic action on gut and bone. Short-acting teduglutide is the only approved GLP-2 analog for the treatment of short-bowel syndrome (SBS). To improve the therapeutic effect, we created a series of lipidated GLP-2R agonists. Experimental Approach: Six GLP-2 analogs were studied in vitro for cAMP accumulation, β-arrestin 1 and 2 recruitment, affinity, and internalization. The trophic actions on intestine and bone were examined in vivo in rodents. Key Results: Lipidations at lysines introduced at position 12, 16, and 20 of hGLP-2(1−33) were well-tolerated with less than 2.2-fold impaired potency and full efficacy at the hGLP-2R in cAMP accumulation. In contrast, N- and C-terminal (His1 and Lys30) lipidations impaired potency by 4.2- and 45-fold and lowered efficacy to 77% and 85% of hGLP-2, respectively. All variants were similarly active on the rat and mouse GLP-2Rs and the three most active variants displayed increased selectivity for hGLP-2R over hGLP-1R activation, compared to native hGLP-2. Impact on arrestin recruitment and receptor internalization followed that of Gαs-coupling, except for lipidation in position 20, where internalization was more impaired, suggesting desensitization protection. A highly active variant (C16 at position 20) with low internalization and a half-life of 9.5 h in rats showed improved gut and bone tropism with increased weight of small intestine in mice and decreased CTX levels in rats. Conclusion and implication: We present novel hGLP-2 agonists suitable for in vivo studies of the GLP-2 system to uncover its pharmacological potential.

OriginalsprogEngelsk
Artikelnummer114383
TidsskriftBiomedicine and Pharmacotherapy
Vol/bind160
Antal sider13
ISSN0753-3322
DOI
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
We would like to thank Maibritt Sigvardt Baggesen, Søren Petersen, Adrian Dragan, Lene Brus Albæk, and Tabatha Emilia de A Constantini for their indispensable technical assistance. This work is supported by the Innovation Fund Denmark (grant number 9065–00181B ); the Danish Diabetes Academy , funded by the Novo Nordisk Foundation , (grant number NNF17SA0031406 ), and from Bainan Biotech, which is supported by the BioInnovation Institute. JAW and SPS are supported by Bainan Biotech. JJH and BH are supported from an unrestricted grant from the Novo Nordisk Foundation Center for Basic Metabolic Research (an independent research institution based at the University of Copenhagen). MMR has received funding from the EFSD/Lilly European Diabetes Research Programme, the Carlsberg Foundation , the Novo Nordisk Foundation ( NNF21OC0070347 ), the Lundbeck Foundation (large project grant R242–2017-409 ) and the Independent Research Fund Denmark ( 9039–00298B ).

Funding Information:
We would like to thank Maibritt Sigvardt Baggesen, Søren Petersen, Adrian Dragan, Lene Brus Albæk, and Tabatha Emilia de A Constantini for their indispensable technical assistance. This work is supported by the Innovation Fund Denmark (grant number 9065–00181B); the Danish Diabetes Academy, funded by the Novo Nordisk Foundation, (grant number NNF17SA0031406), and from Bainan Biotech, which is supported by the BioInnovation Institute. JAW and SPS are supported by Bainan Biotech. JJH and BH are supported from an unrestricted grant from the Novo Nordisk Foundation Center for Basic Metabolic Research (an independent research institution based at the University of Copenhagen). MMR has received funding from the EFSD/Lilly European Diabetes Research Programme, the Carlsberg Foundation, the Novo Nordisk Foundation (NNF21OC0070347), the Lundbeck Foundation (large project grant R242–2017-409) and the Independent Research Fund Denmark (9039–00298B).

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© 2023

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