Semaglutide: Difference between revisions

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[[Image:Semaglutide Artwork.PNG|thumb|Semaglutide (in blue) [[4zgm]] (scroll down for interactive figures)]]
[[Image:Semaglutide Artwork.PNG|thumb|Semaglutide (in blue) [[4zgm]] (scroll down for interactive figures)]]


Semaglutide is an analog of the GLP-1 (glucagon-like peptide 1) hormone. It acts as an agonist to the GLP-1 receptor ([[GLP-1R]]) and is used as drug to manage diabetes. Its use has been growing as a weight-loss medication, and potential benefits across a wide range of diseases is currently studied.
'''Semaglutide''' is an analog of the GLP-1 (glucagon-like peptide 1) hormone. It acts as an agonist to the GLP-1 receptor ([[GLP-1R]]) and is used as drug to manage diabetes. Its use has been growing as a weight-loss medication, and potential benefits across a wide range of diseases is currently studied.


==Discovery==
==Discovery==
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The primary structure of GLP-1 and of semaglutide are shown below. Semaglutide has a non-canonical amino acid in position 8 (corresponding to the second amino acid in the mature 7-37 peptide hormone). A fatty acid is attached is attached to the single lysine in semaglutide via a linker.
The primary structure of GLP-1 and of semaglutide are shown below. Semaglutide has a non-canonical amino acid in position 8 (corresponding to the second amino acid in the mature 7-37 peptide hormone). A fatty acid is attached is attached to the single lysine in semaglutide via a linker.


[[Image:GLP-1 semaglutide.png|600px]]
[[Image:GLP-1 semaglutide.png|thumb|600px]]


Bound to the GLP-1 receptor, the peptide forms a single <scene name='10/1062575/Semaglutide/1'>alpha helix</scene>, just like <scene name='10/1067195/Glp1_only/1'>GLP-1</scene>.  
Bound to the GLP-1 receptor, the peptide forms a single <scene name='10/1062575/Semaglutide/1'>alpha helix</scene>, just like <scene name='10/1067195/Glp1_only/1'>GLP-1</scene>.  
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<text>☼</text>
<text>☼</text>
</jmolLink>
</jmolLink>
</jmol>) of the peptide agonist binds deeply into the transmembrane portion while the C-terminal residues (<jmol>
</jmol>) of the peptide agonist bind deeply into the transmembrane portion while the C-terminal residues (<jmol>
<jmolLink>
<jmolLink>
<script>
<script>
moveto 0.5 { -177 533 827 176.47} 305.9 0.0 0.0 {100.67477777777776 116.59377777777777 171.48799999999997} 123.29278847940834 {0 0 0} 0 0 0 3.0 0.0 0.0;
define current selected;
define current selected;
select 27-37 and chain=P;  
select 27-37 and chain=P;  
selectionHalos on;  
selectionHalos on;  
delay 0.5;  
delay 1.0;  
selectionHalos off;
selectionHalos off;
select current;
select current;
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<jmolLink>
<jmolLink>
<script>
<script>
moveto 0.5 { -116 -575 -810 168.51} 1237.54 0.0 0.0 {100.67477777777776 116.59377777777777 171.48799999999997} 123.29278847940834 {0 0 0} 0 0 0 3.0 0.0 0.0;
define current selected;
define current selected;
select 26:P;  
select 26:P;  
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<jmolLink>
<jmolLink>
<script>
<script>
moveto 0.3 { -116 -575 -810 168.51} 1237.54 -23.77 -24.63 {100.67477777777776 116.59377777777777 171.48799999999997} 123.29278847940834 {0 0 0} 0 0 0 3.0 0.0 0.0;
define current selected;
define current selected;
select 101:P;  
select 101:P;  
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</jmol>) to be attached without interfering with receptor binding.
</jmol>) to be attached without interfering with receptor binding.


Interactions of the <scene name='10/1062575/Semaglutide_and_receptor/4'>C-terminal part of semaglutide with the extracellular domain</scene> include a hydrophobic patch (<jmol>
Interactions of the <jmol>
<jmolLink>
<script>
moveto 1.0 { -864 363 349 132.79} 1354.39 0.0 0.0 {99.33772727272726 108.23119318181817 176.4468181818181} 129.71704236754204 {0 0 0} 0 0 0 3.0 0.0 0.0;
script /scripts/10/1062575/Semaglutide_and_receptor/4.spt
</script>
<text>C-terminal part of semaglutide with the extracellular domain</text>
</jmolLink>
</jmol>include a hydrophobic patch (<jmol>
<jmolLink>
<jmolLink>
<script>
<script>
moveto 0.5 { -654 447 610 145.0} 1024.11 0.0 0.0 {99.33772727272726 108.23119318181817 176.4468181818181} 129.71704236754204 {0 0 0} 0 0 0 3.0 0.0 0.0;
define current selected;
define current selected;
select ((28,29, 31,32) and chain=P) or ((39,88-91, 214) and chain=R)
select ((28,29, 31,32) and chain=P) or ((39,88-91, 214) and chain=R)
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<jmolLink>
<jmolLink>
<script>
<script>
moveto 1.0 { -861 293 415 125.65} 1024.11 6.0 15.44 {99.33772727272726 108.23119318181817 176.4468181818181} 129.71704236754204 {0 0 0} 0 0 0 3.0 0.0 0.0;
define current selected;
define current selected;
select 36:P or 68:R;
select 36:P or 68:R;
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<text>☼</text>
<text>☼</text>
</jmolLink>
</jmolLink>
</jmol>), and hydrogen bonds. Interactions of the <scene name='10/1062575/Semaglutide_and_receptor/7'>N-terminal domain of semaglutide with the transmembrane helices</scene> are extensive, including a hydrophobic patch in the receptor accommodating phenylalanine 12 (<jmol>
</jmol>), and hydrogen bonds. Interactions of the <jmol>
<jmolLink>
<jmolLink>
<script>
<script>
moveto 1.0 { -912 297 281 124.97} 726.1 -1.14 -11.14 {109.93813084112149 120.8334205607477 156.36937383177562} 106.47485918259859 {0 0 0} 0 0 0 3.0 0.0 0.0;
script /scripts/10/1062575/Semaglutide_and_receptor/7.spt
</script>
<text>N-terminal domain of semaglutide with the transmembrane helices</text>
</jmolLink>
</jmol> are extensive, including a hydrophobic patch in the receptor accommodating phenylalanine 12 (<jmol>
<jmolLink>
<script>
moveto 1.0 { -977 186 104 122.83} 726.1 -1.14 -11.14 {109.93813084112149 120.8334205607477 156.36937383177562} 106.47485918259859 {0 0 0} 0 0 0 3.0 0.0 0.0;
define current selected;
define current selected;
select 12:P;  
select 12:P;  
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<jmolLink>
<jmolLink>
<script>
<script>
moveto 1.0 { -685 -507 -522 122.57} 726.1 -1.39 -28.05 {109.93813084112149 120.8334205607477 156.36937383177562} 106.47485918259859 {0 0 0} 0 0 0 3.0 0.0 0.0;
define current selected;
define current selected;
select 7:P or 234:R or 241:R;  
select 7:P or 234:R or 241:R;  
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<jmolLink>
<jmolLink>
<script>
<script>
moveto 1.0 { -969 -113 -218 100.02} 1104.31 -7.13 -63.05 {109.93813084112149 120.8334205607477 156.36937383177562} 106.47485918259859 {0 0 0} 0 0 0 3.0 0.0 0.0;
define current selected;
define current selected;
select 9:P or 190:R;  
select 9:P or 190:R;  
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==Half-life==
==Half-life==
GLP-1 has a half-life of about two minutes in the bloodstream, and thus is unsuitable as medication unless administered continually. GLP-1 is initially degraded by dipeptidyl peptidase IV (DPP-4), a serine protease expressed on the surface of cells throughout the body<ref>PMID: 26284071</ref>. DPP-4 exists both as a membrane-bound enzyme and in a free form, released into circulation through a process called shedding. Like chymotrypsin, DPP-4 has a unique active site with a catalytic triad. Different from chymotrypsin, DPP-4 is an exoprotease, capable of recognizing and <scene name='10/1062575/Glp1_only/1'>cleaving</scene> peptides with a proline or alanine residue in the second position, thus removing a dipeptide.  
GLP-1 has a half-life of about two minutes in the bloodstream, and thus is unsuitable as medication unless administered continually. GLP-1 is initially degraded by [[dipeptidyl peptidase IV]] (DPP-4), a serine protease expressed on the surface of cells throughout the body<ref>PMID: 26284071</ref>. DPP-4 exists both as a membrane-bound enzyme and in a free form, released into circulation through a process called shedding. Like chymotrypsin, DPP-4 has a unique active site with a catalytic triad. Different from chymotrypsin, DPP-4 is an exoprotease, capable of recognizing and <scene name='10/1062575/Glp1_only/1'>cleaving</scene> peptides with a proline or alanine residue in the second position, thus removing a dipeptide.  
   
   
[[Image:GLP1 DPP4 processing.png|600px]]
[[Image:GLP1 DPP4 processing.png|600px]]
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==Medical use of Semaglutide==
==Medical use of Semaglutide==
Semaglutide medications (Ozempic, Wegovy, and Rybelsus) have become extremely popular over time in managing weight loss and obesity. Originally developed as treatments for type 2 diabetes, medications such as Ozempic are now widely used for their ability to aid weight loss. As a GLP-1 receptor agonist (GLP-1 RA), semaglutide works by mimicking the effects of the GLP-1 hormone in the body. This action helps regulate the metabolic system, control appetite, and reduce calorie intake, leading to significant weight loss in many users. Semaglutide also slows gastric emptying, which prolongs the feeling of fullness after eating and further supports weight management. 
Semaglutide medications (Ozempic, Wegovy, and Rybelsus) have become extremely popular over time in managing weight loss and obesity. A KFF poll conducted in May 2024 found that 1 in 8 respondents (adults in the United States) say that they have taken a GLP-1 agonist in the past <ref>Harris E. Poll: Roughly 12% of US Adults Have Used a GLP-1 Drug, Even If Unaffordable. JAMA. 2024;332(1):8. DOI:10.1001/jama.2024.10333</ref>. Originally developed as treatments for type 2 diabetes, medications such as Ozempic are now widely used for their ability to aid weight loss. As a GLP-1 receptor agonist (GLP-1 RA), semaglutide works by mimicking the effects of the GLP-1 hormone in the body. This action helps regulate the metabolic system, control appetite, and reduce calorie intake, leading to significant weight loss in many users. Semaglutide also slows gastric emptying, which prolongs the feeling of fullness after eating and further supports weight management. 


==Side effects==
==Side effects==
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Novikoff, Aaron et al. Why are we still in need for novel anti-obesity medications? The Lancet Regional Health – Europe, Volume 47, 101098
Novikoff, Aaron et al. Why are we still in need for novel anti-obesity medications? The Lancet Regional Health – Europe, Volume 47, 101098
[https://doi.org/10.1016/j.lanepe.2024.101098 DOI:10.1016/j.lanepe.2024.101098]</ref>.
[https://doi.org/10.1016/j.lanepe.2024.101098 DOI:10.1016/j.lanepe.2024.101098]</ref>.
==3D structures of semaglutide==
Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
[[7ki0]] - hSG + GLP-1 receptor + Gs proteins + nobody - human - Cryo EM<br />
[[7ki1]] - hTaspoglutide + GLP-1 receptor + Gs proteins + nobody - human - Cryo EM<br />
[[4zgm]] - hSG + GLP-1 receptor


==Student contributors==
==Student contributors==
This page was created as a two-week project of an undergraduate biochemistry course. Karsten Theis would like to acknowledge contributors to the Structure, Half-life and Side effects sections, Paige, Marissa, Faith McCormack, William Buckley, Humzah, Mahrosha, Evelyn, Naba Algertani, Faiza, Sara, and Natalisha.  
This page was created as a two-week project of an undergraduate biochemistry course. Karsten Theis would like to acknowledge contributors to the Structure, Half-life and Side effects sections, Paige, Marissa, Faith McCormack, William Buckley, Humzah, Mahrosha, Evelyn, Naba Algertani, Faiza Abdullah, Sara, and Natalisha.  


== References ==
== References ==
<references/>
<references/>
[[Category:Topic Page]]
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