Semaglutide

Semaglutide is a synthetic analogue of glucagon-like peptide-1 (GLP-1): 31 amino acids with two substitutions and a C18 fatty diacid chain on lysine 26 that binds serum albumin. Published work on semaglutide runs from the medicinal chemistry behind its design to receptor pharmacology and large clinical trials in type 2 diabetes and obesity.

Reading the structure on the certificate

The certificate writes semaglutide as H-H-Aib-EGTFTSDVSSYLEGQAAK(2×OEG-γGlu-C18 diacid)EFIAWLVRGRG-OH. The first H- is the free N-terminus, so the chain starts with histidine, and the residues follow GLP-1 numbering: Aib sits at position 8, which puts the histidine at 7 and the end of the 31-residue chain at 37. Lau and colleagues described two substitutions relative to human GLP-1, Aib (alpha-aminoisobutyric acid) at 8 and arginine at 34, with lysine 26 derivatised¹. Because position 34 is arginine, lysine 26 is the only lysine in the sequence, and it carries the whole side chain: a γ-glutamic acid, two OEG spacers and octadecanedioic acid, an 18-carbon diacid. The C-terminus is a free acid.

That side chain is why the theoretical mass, 4113.6 Da, sits well above what the amino acids alone would add up to, and the LC-MS identity result on the certificate is the figure to hold against it. The same mass converts the fill to moles: 5 mg is about 1.2 µmol, slightly less in practice because the powder also contains the residual water the certificate reports.

Hazard classification and storage

Semaglutide carries a hazard classification. Its safety data sheet lists it as Carc. 2 (H351, suspected of causing cancer) and Repr. 2 (H361, suspected of damaging fertility or the unborn child), and asks for the container to be kept tightly closed, labelled and locked up, out of reach of unauthorised persons. Store the sealed vial at −20 °C, desiccated and away from light, and let it warm to room temperature before opening so that moisture does not condense on the powder. Reconstituted solution goes to 2 to 8 °C, protected from light, for a period your laboratory has set. General practice for keeping peptides is covered in peptide storage and stability.

What the research covers

Designed around albumin binding

Semaglutide grew out of liraglutide, an acylated GLP-1 analogue that binds serum albumin and was already approved for diabetes and obesity¹. In the 2015 discovery paper, Lau and colleagues aimed for a longer-acting successor by raising albumin affinity and making the peptide fully stable against metabolic degradation¹. They found that the fatty acid and the chemistry linking it to the peptide decided three things at once: albumin affinity, GLP-1 receptor potency and how long exposure lasted¹.

The chosen compound gave up some receptor binding to get there. Its affinity for the GLP-1 receptor was 0.38 ± 0.06 nM, a threefold drop from liraglutide, while albumin affinity rose¹. Given intravenously to mini-pigs, it had a plasma half-life of 46.1 hours¹. Semaglutide was in phase 3 testing when the paper appeared¹, and it is now approved as a prescription medicine in a number of markets. The vial sold here is a research chemical, not one of those approved products.

Signalling at the GLP-1 receptor

Activation of the GLP-1 receptor can be read out in more than one way. Willard and colleagues followed it through cAMP generation, β-arrestin recruitment and receptor internalisation, and found that tirzepatide favoured cAMP over β-arrestin and internalised the receptor less than native GLP-1 did². In primary islets, β-arrestin1 limited the insulin response to GLP-1². The abstract makes these comparisons against native GLP-1 and reports no semaglutide data².

Semaglutide as a comparator

Newer incretin drugs have been tested head to head against semaglutide. SURPASS-2 was an open-label, 40-week phase 3 trial that randomly assigned 1,879 adults with type 2 diabetes in equal numbers to three tirzepatide arms or to semaglutide³. At baseline the mean glycated haemoglobin was 8.28%, the mean age 56.6 years and the mean weight 93.7 kg³. Its primary endpoint was the change in glycated haemoglobin from baseline to week 40³. Each tirzepatide arm was noninferior and superior to the semaglutide arm, with estimated differences of 0.15 to 0.45 percentage points³. The semaglutide trial programmes in diabetes, obesity and cardiovascular outcomes are described in the semaglutide guide; their primary papers are not in this page's reference list.

What is not established

The receptor affinity and half-life figures come from the discovery paper's own assays and from mini-pigs¹, and the clinical paper cited here uses semaglutide as the comparator rather than the subject. SURPASS-2 was also open-label, so participants and investigators knew which drug each arm received³. No paper on this page measured how long semaglutide stays intact after a freeze-dried vial is dissolved. Reviews of protein stability handle chemical and physical degradation as separate problems and discuss stabilisation in solution and in the dried state⁴, but they give no figure for this peptide. None of the studies used SCALE Performance material.

Frequently asked questions

References

1. Lau J, Bloch P, Schäffer L, et al. Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide. J Med Chem. 2015;58(18):7370-80. DOI · PubMed
2. Willard FS, Douros JD, Gabe MB, et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 2020;5(17). DOI · PubMed
3. Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021;385(6):503-515. DOI · PubMed
4. Manning MC, Chou DK, Murphy BM, et al. Stability of protein pharmaceuticals: an update. Pharm Res. 2010;27(4):544-75. DOI · PubMed