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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Can Semaglutide Bind Tighter to GLP-1R?

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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Renoprotective Effects of Incretin-Based Therapy in Diabetes Mellitus

BioMed Research International ◽

10.1155/2021/8163153 ◽

2021 ◽

Vol 2021 ◽

pp. 1-7

Author(s):

Habib Yaribeygi ◽

Stephen L. Atkin ◽

Fabrizio Montecucco ◽

Tannaz Jamialahmadi ◽

Amirhossein Sahebkar

Keyword(s):

Diabetic Nephropathy ◽

Glycemic Control ◽

Scientific Evidence ◽

Glucagon Secretion ◽

Receptor Agonists ◽

Beneficial Effects ◽

Reduce Blood Glucose ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

A Minor

Glucagon-like peptide-1 (GLP-1) receptor agonists are recently discovered antidiabetic drugs with potent hypoglycemic effects. Among different mechanisms of activity, these compounds were shown to reduce blood glucose by suppression of glucagon secretion and stimulation of glucose-dependent insulin secretion. These antidiabetic agents have a minor risk of hypoglycemia and have been suggested as a second-line therapy to be added to metformin treatment to further optimize glycemic control in diabetes. More recently, scientific evidence suggests that GLP-1 receptor agonists may particularly afford protection from diabetic nephropathy through modulation of the molecular pathways involved in renal impairment and so improve renal function. This additional benefit adds further weight for these compounds to become promising drugs not only for glycemic control but also to prevent diabetic complications. In this review, we have updated evidence on the beneficial effects of GLP-1 receptor agonists on diabetic nephropathy and detailed the underlying pathophysiological mechanisms.

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