Semaglutide: Difference between revisions

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==Structure==

==Structure and binding to GLP-1R==

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~~ peptide forms a single alpha helix, just like GLP-1.

[[Image:GLP-1 semaglutide.png|700px]]

==~~Binding to receptor~~==

Bound to the GLP-1 receptor, the peptide forms a single alpha helix, just like GLP-1.

==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 cleaving peptides with a proline or alanine residue in the second position, thus removing a dipeptide.

[[Image:GLP1 DPP4 processing.png|600px]]

Synthetic agonists like semaglutide are engineered to resist degradation by DPP-4. The drug developers substituted Alanine-8 with aminoisobutyric acid (Alb) and added a stabilizing fatty acid chain at lysine-26. These modifications alter the recognition sequence for the DPP-4’s active site and the fatty acid chain allows the protein to bind to albumin, which prolongs the drugs’ stability in the bloodstream. DPP-4 inhibitors are useful to decrease the enzyme’s total activity (resulting in a higher GLP-1 concentration), and are administered on their own or in combination with synthetic agonists. The inhibitors come in multiple forms, all in the gliptin class, and these competitively inhibit DPP-4 by binding to its active site instead of GLP-1 or analogs.

</StructureSection>

==Synthesis==

Semaglutide is made by Novo Nordisc, and the details are proprietary. The product is semisynthetic, with the bulk of the peptide made in recombinant yeast<ref name="euro">Committee for Medicinal Products for Human use (CHMP). European Medicines Agency (EMA). (2018).

https://www.ema.europa.eu/en/documents/assessment-report/ozempic-epar-public-assessment-report_en.pdf</ref> and the fatty acid and the first two amino acids attached afterwards. Because the second lysine of GLP-1 is replaced by an arginine in semaglutide, the fatty acid is attached to a single lysine, simplifying the coupling between peptide and linker-attached fatty acid.

==Medical use of Semaglutide==

Line 24:

Line 38:

[[Image:Semaglutide side effects.png|600px]]

The bar chart depicts the proportion of patients experiencing common adverse events (AEs) during Phase 3a trials for semaglutide (0.5 mg and 1.0 mg) compared to other treatments, including exenatide ER and insulin glargine. The AEs include gastrointestinal disorders (nausea, vomiting, diarrhea, constipation), nasopharyngitis, fatigue, and headache. Data are presented as adjusted percentages, with odds ratios (OR) and confidence intervals (CI) providing additional context. OR values above 1.0 suggest a higher likelihood of AEs with semaglutide, while CIs indicate the range of variability and precision. The results show that semaglutide, particularly at the 1.0 mg dose, is associated with a higher frequency of gastrointestinal AEs compared to comparators. Neurological side effects, such as headache and fatigue, and nasopharyngitis were also more common in semaglutide groups. These findings underscore the dose-dependent nature of AEs with semaglutide and the importance of balancing its efficacy in weight loss with patient tolerability.<ref~~>Committee for Medicinal Products for Human use (CHMP). European Medicines Agency (EMA). (2018).~~

The bar chart depicts the proportion of patients experiencing common adverse events (AEs) during Phase 3a trials for semaglutide (0.5 mg and 1.0 mg) compared to other treatments, including exenatide ER and insulin glargine. The AEs include gastrointestinal disorders (nausea, vomiting, diarrhea, constipation), nasopharyngitis, fatigue, and headache. Data are presented as adjusted percentages, with odds ratios (OR) and confidence intervals (CI) providing additional context. OR values above 1.0 suggest a higher likelihood of AEs with semaglutide, while CIs indicate the range of variability and precision. The results show that semaglutide, particularly at the 1.0 mg dose, is associated with a higher frequency of gastrointestinal AEs compared to comparators. Neurological side effects, such as headache and fatigue, and nasopharyngitis were also more common in semaglutide groups. These findings underscore the dose-dependent nature of AEs with semaglutide and the importance of balancing its efficacy in weight loss with patient tolerability.<ref name="euro"/>

~~https:~~/~~/www.ema.europa.eu/en/documents/assessment-report/ozempic-epar-public-assessment-report_en.pdf</ref~~>

While semaglutide is effective for weight loss, these findings emphasize the need to balance therapeutic benefits with patient tolerability, tailoring treatment plans to minimize side effects while achieving optimal outcomes.

Semaglutide: Difference between revisions

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@@ Line 8: / Line 8: @@
 <StructureSection load='4ZGM' size='340' side='right' caption='Caption for this structure' scene='10/1062575/Semaglutide_peptide/1'>
-==Structure==
+==Structure and binding to GLP-1R==
+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 peptide forms a single alpha helix, just like GLP-1.
+[[Image:GLP-1 semaglutide.png|700px]]
-==Binding to receptor==
+Bound to the GLP-1 receptor, the peptide forms a single alpha helix, just like GLP-1.
+==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 cleaving peptides with a proline or alanine residue in the second position, thus removing a dipeptide.
+[[Image:GLP1 DPP4 processing.png|600px]]
+Synthetic agonists like semaglutide are engineered to resist degradation by DPP-4. The drug developers substituted Alanine-8 with aminoisobutyric acid (Alb) and added a stabilizing fatty acid chain at lysine-26. These modifications alter the recognition sequence for the DPP-4’s active site and the fatty acid chain allows the protein to bind to albumin, which prolongs the drugs’ stability in the bloodstream. DPP-4 inhibitors are useful to decrease the enzyme’s total activity (resulting in a higher GLP-1 concentration), and are administered on their own or in combination with synthetic agonists. The inhibitors come in multiple forms, all in the gliptin class, and these competitively inhibit DPP-4 by binding to its active site instead of GLP-1 or analogs.
 </StructureSection>
+==Synthesis==
+Semaglutide is made by Novo Nordisc, and the details are proprietary. The product is semisynthetic, with the bulk of the peptide made in recombinant yeast<ref name="euro">Committee for Medicinal Products for Human use (CHMP). European Medicines Agency (EMA). (2018).
+https://www.ema.europa.eu/en/documents/assessment-report/ozempic-epar-public-assessment-report_en.pdf</ref> and the fatty acid and the first two amino acids attached afterwards. Because the second lysine of GLP-1 is replaced by an arginine in semaglutide, the fatty acid is attached to a single lysine, simplifying the coupling between peptide and linker-attached fatty acid.
 ==Medical use of Semaglutide==
@@ Line 24: / Line 38: @@
 [[Image:Semaglutide side effects.png|600px]]
-The bar chart depicts the proportion of patients experiencing common adverse events (AEs) during Phase 3a trials for semaglutide (0.5 mg and 1.0 mg) compared to other treatments, including exenatide ER and insulin glargine. The AEs include gastrointestinal disorders (nausea, vomiting, diarrhea, constipation), nasopharyngitis, fatigue, and headache. Data are presented as adjusted percentages, with odds ratios (OR) and confidence intervals (CI) providing additional context. OR values above 1.0 suggest a higher likelihood of AEs with semaglutide, while CIs indicate the range of variability and precision. The results show that semaglutide, particularly at the 1.0 mg dose, is associated with a higher frequency of gastrointestinal AEs compared to comparators. Neurological side effects, such as headache and fatigue, and nasopharyngitis were also more common in semaglutide groups. These findings underscore the dose-dependent nature of AEs with semaglutide and the importance of balancing its efficacy in weight loss with patient tolerability.<ref>Committee for Medicinal Products for Human use (CHMP). European Medicines Agency (EMA). (2018).
+The bar chart depicts the proportion of patients experiencing common adverse events (AEs) during Phase 3a trials for semaglutide (0.5 mg and 1.0 mg) compared to other treatments, including exenatide ER and insulin glargine. The AEs include gastrointestinal disorders (nausea, vomiting, diarrhea, constipation), nasopharyngitis, fatigue, and headache. Data are presented as adjusted percentages, with odds ratios (OR) and confidence intervals (CI) providing additional context. OR values above 1.0 suggest a higher likelihood of AEs with semaglutide, while CIs indicate the range of variability and precision. The results show that semaglutide, particularly at the 1.0 mg dose, is associated with a higher frequency of gastrointestinal AEs compared to comparators. Neurological side effects, such as headache and fatigue, and nasopharyngitis were also more common in semaglutide groups. These findings underscore the dose-dependent nature of AEs with semaglutide and the importance of balancing its efficacy in weight loss with patient tolerability.<ref name="euro"/>
-https://www.ema.europa.eu/en/documents/assessment-report/ozempic-epar-public-assessment-report_en.pdf</ref>
 While semaglutide is effective for weight loss, these findings emphasize the need to balance therapeutic benefits with patient tolerability, tailoring treatment plans to minimize side effects while achieving optimal outcomes.