GLP-1 Val8: A Biased GLP-1R Agonist with Altered Binding Kinetics and Impaired Release of Pancreatic Hormones in Rats

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Standard

GLP-1 Val8 : A Biased GLP-1R Agonist with Altered Binding Kinetics and Impaired Release of Pancreatic Hormones in Rats. / van der Velden, Wijnand J C; Smit, Florent X; Christiansen, Charlotte B; Møller, Thor C; Hjortø, Gertrud M; Larsen, Olav; Schiellerup, Sine P; Bräuner-Osborne, Hans; Holst, Jens J; Hartmann, Bolette; Frimurer, Thomas M; Rosenkilde, Mette M.

I: ACS Pharmacology & Translational Science, Bind 4, Nr. 1, 2021, s. 296-313.

Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt

Harvard

van der Velden, WJC, Smit, FX, Christiansen, CB, Møller, TC, Hjortø, GM, Larsen, O, Schiellerup, SP, Bräuner-Osborne, H, Holst, JJ, Hartmann, B, Frimurer, TM & Rosenkilde, MM 2021, 'GLP-1 Val8: A Biased GLP-1R Agonist with Altered Binding Kinetics and Impaired Release of Pancreatic Hormones in Rats', ACS Pharmacology & Translational Science, bind 4, nr. 1, s. 296-313. https://doi.org/10.1021/acsptsci.0c00193

APA

van der Velden, W. J. C., Smit, F. X., Christiansen, C. B., Møller, T. C., Hjortø, G. M., Larsen, O., Schiellerup, S. P., Bräuner-Osborne, H., Holst, J. J., Hartmann, B., Frimurer, T. M., & Rosenkilde, M. M. (2021). GLP-1 Val8: A Biased GLP-1R Agonist with Altered Binding Kinetics and Impaired Release of Pancreatic Hormones in Rats. ACS Pharmacology & Translational Science, 4(1), 296-313. https://doi.org/10.1021/acsptsci.0c00193

Vancouver

van der Velden WJC, Smit FX, Christiansen CB, Møller TC, Hjortø GM, Larsen O o.a. GLP-1 Val8: A Biased GLP-1R Agonist with Altered Binding Kinetics and Impaired Release of Pancreatic Hormones in Rats. ACS Pharmacology & Translational Science. 2021;4(1):296-313. https://doi.org/10.1021/acsptsci.0c00193

Author

van der Velden, Wijnand J C ; Smit, Florent X ; Christiansen, Charlotte B ; Møller, Thor C ; Hjortø, Gertrud M ; Larsen, Olav ; Schiellerup, Sine P ; Bräuner-Osborne, Hans ; Holst, Jens J ; Hartmann, Bolette ; Frimurer, Thomas M ; Rosenkilde, Mette M. / GLP-1 Val8 : A Biased GLP-1R Agonist with Altered Binding Kinetics and Impaired Release of Pancreatic Hormones in Rats. I: ACS Pharmacology & Translational Science. 2021 ; Bind 4, Nr. 1. s. 296-313.

Bibtex

@article{bc95527a26564194bc79f4e4a789cb1c,
title = "GLP-1 Val8: A Biased GLP-1R Agonist with Altered Binding Kinetics and Impaired Release of Pancreatic Hormones in Rats",
abstract = "Biased ligands that selectively confer activity in one pathway over another are pharmacologically important because biased signaling may reduce on-target side effects and improve drug efficacy. Here, we describe an N-terminal modification in the incretin hormone glucagon-like peptide (GLP-1) that alters the signaling capabilities of the GLP-1 receptor (GLP-1R) by making it G protein biased over internalization but was originally designed to confer DPP-4 resistance and thereby prolong the half-life of GLP-1. Despite similar binding affinity, cAMP production, and calcium mobilization, substitution of a single amino acid (Ala8 to Val8) in the N-terminus of GLP-1(7-36)NH2 (GLP-1 Val8) severely impaired its ability to internalize GLP-1R compared to endogenous GLP-1. In-depth binding kinetics analyses revealed shorter residence time for GLP-1 Val8 as well as a slower observed association rate. Molecular dynamics (MD) displayed weaker and less interactions of GLP-1 Val8 with GLP-1R, as well as distinct conformational changes in the receptor compared to GLP-1. In vitro validation of the MD, by receptor alanine substitutions, confirmed stronger impairments of GLP-1 Val8-mediated signaling compared to GLP-1. In a perfused rat pancreas, acute stimulation with GLP-1 Val8 resulted in a lower insulin and somatostatin secretion compared to GLP-1. Our study illustrates that profound differences in molecular pharmacological properties, which are essential for the therapeutic targeting of the GLP-1 system, can be induced by subtle changes in the N-terminus of GLP-1. This information could facilitate the development of optimized GLP-1R agonists.",
author = "{van der Velden}, {Wijnand J C} and Smit, {Florent X} and Christiansen, {Charlotte B} and M{\o}ller, {Thor C} and Hjort{\o}, {Gertrud M} and Olav Larsen and Schiellerup, {Sine P} and Hans Br{\"a}uner-Osborne and Holst, {Jens J} and Bolette Hartmann and Frimurer, {Thomas M} and Rosenkilde, {Mette M}",
year = "2021",
doi = "10.1021/acsptsci.0c00193",
language = "English",
volume = "4",
pages = "296--313",
journal = "ACS Pharmacology and Translational Science",
issn = "2575-9108",
publisher = "ACS Publications",
number = "1",

}

RIS

TY - JOUR

T1 - GLP-1 Val8

T2 - A Biased GLP-1R Agonist with Altered Binding Kinetics and Impaired Release of Pancreatic Hormones in Rats

AU - van der Velden, Wijnand J C

AU - Smit, Florent X

AU - Christiansen, Charlotte B

AU - Møller, Thor C

AU - Hjortø, Gertrud M

AU - Larsen, Olav

AU - Schiellerup, Sine P

AU - Bräuner-Osborne, Hans

AU - Holst, Jens J

AU - Hartmann, Bolette

AU - Frimurer, Thomas M

AU - Rosenkilde, Mette M

PY - 2021

Y1 - 2021

N2 - Biased ligands that selectively confer activity in one pathway over another are pharmacologically important because biased signaling may reduce on-target side effects and improve drug efficacy. Here, we describe an N-terminal modification in the incretin hormone glucagon-like peptide (GLP-1) that alters the signaling capabilities of the GLP-1 receptor (GLP-1R) by making it G protein biased over internalization but was originally designed to confer DPP-4 resistance and thereby prolong the half-life of GLP-1. Despite similar binding affinity, cAMP production, and calcium mobilization, substitution of a single amino acid (Ala8 to Val8) in the N-terminus of GLP-1(7-36)NH2 (GLP-1 Val8) severely impaired its ability to internalize GLP-1R compared to endogenous GLP-1. In-depth binding kinetics analyses revealed shorter residence time for GLP-1 Val8 as well as a slower observed association rate. Molecular dynamics (MD) displayed weaker and less interactions of GLP-1 Val8 with GLP-1R, as well as distinct conformational changes in the receptor compared to GLP-1. In vitro validation of the MD, by receptor alanine substitutions, confirmed stronger impairments of GLP-1 Val8-mediated signaling compared to GLP-1. In a perfused rat pancreas, acute stimulation with GLP-1 Val8 resulted in a lower insulin and somatostatin secretion compared to GLP-1. Our study illustrates that profound differences in molecular pharmacological properties, which are essential for the therapeutic targeting of the GLP-1 system, can be induced by subtle changes in the N-terminus of GLP-1. This information could facilitate the development of optimized GLP-1R agonists.

AB - Biased ligands that selectively confer activity in one pathway over another are pharmacologically important because biased signaling may reduce on-target side effects and improve drug efficacy. Here, we describe an N-terminal modification in the incretin hormone glucagon-like peptide (GLP-1) that alters the signaling capabilities of the GLP-1 receptor (GLP-1R) by making it G protein biased over internalization but was originally designed to confer DPP-4 resistance and thereby prolong the half-life of GLP-1. Despite similar binding affinity, cAMP production, and calcium mobilization, substitution of a single amino acid (Ala8 to Val8) in the N-terminus of GLP-1(7-36)NH2 (GLP-1 Val8) severely impaired its ability to internalize GLP-1R compared to endogenous GLP-1. In-depth binding kinetics analyses revealed shorter residence time for GLP-1 Val8 as well as a slower observed association rate. Molecular dynamics (MD) displayed weaker and less interactions of GLP-1 Val8 with GLP-1R, as well as distinct conformational changes in the receptor compared to GLP-1. In vitro validation of the MD, by receptor alanine substitutions, confirmed stronger impairments of GLP-1 Val8-mediated signaling compared to GLP-1. In a perfused rat pancreas, acute stimulation with GLP-1 Val8 resulted in a lower insulin and somatostatin secretion compared to GLP-1. Our study illustrates that profound differences in molecular pharmacological properties, which are essential for the therapeutic targeting of the GLP-1 system, can be induced by subtle changes in the N-terminus of GLP-1. This information could facilitate the development of optimized GLP-1R agonists.

U2 - 10.1021/acsptsci.0c00193

DO - 10.1021/acsptsci.0c00193

M3 - Journal article

C2 - 33615180

VL - 4

SP - 296

EP - 313

JO - ACS Pharmacology and Translational Science

JF - ACS Pharmacology and Translational Science

SN - 2575-9108

IS - 1

ER -

ID: 258277851