Can Semaglutide Bind Tighter to GLP-1R?

Mapping Intimacies ◽

10.20944/preprints202007.0582.v1 ◽

2020 ◽

Author(s):

Wei Li

Keyword(s):

Sequence Similarity ◽

Structural Data ◽

Peptide Backbone ◽

Short Article ◽

Downstream Effects ◽

Reduce Blood Glucose ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

First Time

Semaglutide is a glucagon-like peptide 1 analog used for the treatment of patients with type 2 diabetes mellitus. With 94% sequence similarity to human GLP-1, semaglutide is a glucagon-like peptide-1 receptor (GLP-1R) agonist, which binds directly to GLP-1R, causing various beneficial downstream effects that reduce blood glucose. Practically, it is favourable for semaglutide to bind not just directly, but also tighter, to its receptor GLP-1R. Therefore, incorporating currently available experimental structural data of semaglutide-GLP-1R, this short article reports for the first time that biophysically, semaglutide is able to bind tighter to GLP-1R with just a simple Val27-Arg28 exchange in its peptide backbone.

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Strengthening Semaglutide-GLP-1R Binding Affinity Via a Val27-Arg28 Exchange in the Peptide Backbone of Semaglutide: A Computational Structural Approach

Journal of Computational Biophysics and Chemistry ◽

10.1142/s2737416521500289 ◽

2021 ◽

pp. 1-5

Author(s):

Wei Li

Keyword(s):

Sequence Similarity ◽

Structural Data ◽

Testable Hypothesis ◽

Short Paper ◽

Peptide Backbone ◽

Downstream Effects ◽

Biophysical Analysis ◽

Reduce Blood Glucose ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Semaglutide is a glucagon-like peptide 1 analog used for the treatment of patients with type 2 diabetes mellitus. With 94% sequence similarity to human GLP-1, semaglutide is a glucagon-like peptide-1 receptor (GLP-1R) agonist, which binds directly to GLP-1R, causing various beneficial downstream effects that reduce blood glucose. Incorporating currently (June 21, 2021) available experimental structural data in PDB of semaglutide and GLP-1R, and with a set of computational structural and biophysical analysis, this short paper for the first time puts forward an experimentally testable hypothesis: semaglutide is able to bind tighter to GLP-1R via a simple Val27-Arg28 exchange in its peptide backbone.

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miR-7 Regulates GLP-1-Mediated Insulin Release by Targeting β-Arrestin 1

Cells ◽

10.3390/cells9071621 ◽

2020 ◽

Vol 9 (7) ◽

pp. 1621 ◽

Cited By ~ 4

Author(s):

Alessandro Matarese ◽

Jessica Gambardella ◽

Angela Lombardi ◽

Xujun Wang ◽

Gaetano Santulli

Keyword(s):

Insulin Release ◽

Cell Function ◽

Specific Interaction ◽

Β Cells ◽

Β Cell Function ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Glucose Stimulated Insulin Secretion ◽

First Time

Glucagon-like peptide-1 (GLP-1) has been shown to potentiate glucose-stimulated insulin secretion binding GLP-1 receptor on pancreatic β cells. β-arrestin 1 (βARR1) is known to regulate the desensitization of GLP-1 receptor. Mounting evidence indicates that microRNAs (miRNAs, miRs) are fundamental in the regulation of β cell function and insulin release. However, the regulation of GLP-1/βARR1 pathways by miRs has never been explored. Our hypothesis is that specific miRs can modulate the GLP-1/βARR1 axis in β cells. To test this hypothesis, we applied a bioinformatic approach to detect miRs that could target βARR1; we identified hsa-miR-7-5p (miR-7) and we validated the specific interaction of this miR with βARR1. Then, we verified that GLP-1 was indeed able to regulate the transcription of miR-7 and βARR1, and that miR-7 significantly regulated GLP-1-induced insulin release and cyclic AMP (cAMP) production in β cells. Taken together, our findings indicate, for the first time, that miR-7 plays a functional role in the regulation of GLP-1-mediated insulin release by targeting βARR1. These results have a decisive clinical impact given the importance of drugs modulating GLP-1 signaling in the treatment of patients with type 2 diabetes mellitus.

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