Key findings
- The discovery series reported a GLP-1 receptor affinity of 0.38 nM for the selected analogue, three-fold decreased relative to liraglutide, while its albumin affinity was increased. [1]
- Cryo-EM structures of the analogue bound to the GLP-1 receptor and Gs protein showed peptide interactions similar to those of GLP-1, with different motions within the receptor and the bound peptide. [2]
- In rodents the analogue reached the brainstem, septal nucleus and hypothalamus without crossing the blood-brain barrier, interacting with the brain through circumventricular organs and sites adjacent to the ventricles. [3]
- In mice whose Glp1r was inactivated in Tie2-positive endothelial and hematopoietic cells, the reduction in atherosclerosis persisted while a subset of hepatic transcript changes did not. [4]
Identity and structure
- Substitutions
- Aib at position 8 and Arg at position 34 compared with human GLP-1, with derivatization at lysine 26 [1]
- Design intent
- The fatty acid moiety and its linking chemistry to GLP-1 were the features varied to raise albumin affinity while keeping GLP-1 receptor potency [1]
- Form as supplied
- Sterile lyophilized powder
Mechanism as studied
The discovery work presents albumin binding as the basis of prolonged exposure. The authors varied the fatty acid moiety and its linker and reported that these were the features securing both albumin affinity and GLP-1 receptor potency, with the selected analogue trading a three-fold decrease in receptor affinity for the increased albumin affinity. [1]
Cryo-EM and 3D variability analysis of the analogue-bound GLP-1 receptor and Gs complex attributed the difference between two GLP-1 receptor agonists to motion within the receptor and the bound peptides rather than to a different set of peptide contacts. [2]
Rodent work located central access at the circumventricular organs and several sites adjacent to the ventricles, and reported c-Fos activity in ten brain areas including regions such as the lateral parabrachial nucleus where the authors found no direct receptor interaction. [3]
In cultured cardiomyocytes challenged with lipopolysaccharide the authors linked increased survival to AMPK pathway activation, increased autophagy and lower reactive oxygen species production. [5]
Research findings
In vitro
- System
- GLP-1 receptor affinity and serum albumin binding assays across a series of acylated GLP-1 analogues
- Measured
- GLP-1 receptor affinity and albumin affinity
- Reported
- Receptor affinity of the selected analogue was 0.38 ± 0.06 nM, three-fold decreased compared with liraglutide, while albumin affinity was increased. [1]
Preclinical in vivo
- System
- Mini-pigs; the material is the analogue itself rather than a catalog lot
- Measured
- Plasma half-life and mean residence time
- Reported
- Plasma half-life was 46.1 hours and the mean residence time was 63.6 hours. [1]
Structural
- System
- Cryo-EM of GLP-1 receptor and Gs protein complexes bound by this analogue and by taspoglutide
- Measured
- Peptide and receptor conformation, and 3D variability of the complexes
- Reported
- Peptide interactions resembled those of GLP-1, while motions within the receptor and the bound peptides differed between the two analogues. [2]
Preclinical in vivo
- System
- Rodents, with mapping of where the analogue reached the brain, c-Fos immunolabeling across brain areas, behavioural measures of food intake and food preference, and transcriptomic analysis of microdissected brain areas from rats
- Measured
- Food intake and food preference, body weight, energy expenditure, brain access, c-Fos activity, receptor distribution and transcript levels
- Reported
- Body weight fell without a decrease in energy expenditure; the analogue did not cross the blood-brain barrier; c-Fos activity appeared in ten brain areas, and prolactin-releasing hormone and tyrosine hydroxylase transcripts rose in the area postrema. [3]
Preclinical in vivo
- System
- Apolipoprotein E-deficient and LDL receptor-deficient mice fed a Western diet, with aortic gene expression profiling
- Measured
- Plaque lesion development and aortic transcript levels
- Reported
- Plaque lesion development was attenuated, partly independently of weight and cholesterol lowering, and the diet-associated aortic expression changes were significantly reversed. [6]
Preclinical in vivo
- System
- Glp1rTie2-/- mice, with Glp1r inactivated in Tie2-positive endothelial and hematopoietic cells, compared with Glp1rTie2+/+ mice
- Measured
- Atherosclerosis following viral PCSK9 expression, hepatic transcript levels, hepatic triglyceride content and collagen accumulation
- Reported
- Atherosclerosis was reduced in both genotypes, whereas the hepatic transcript, triglyceride and collagen changes occurred only in the mice retaining the receptor in Tie2-positive cells. [4]
In vitro
- System
- H9c2 cardiomyocyte cultures challenged with lipopolysaccharide
- Measured
- Survival by MTT assay, apoptosis, AMPK pathway proteins, autophagy and reactive oxygen species
- Reported
- Survival increased and apoptosis was inhibited at three concentrations; AMPK signaling and autophagy increased and reactive oxygen species production fell. [5]
Handling for in-vitro work
- Serum albumin in the cited work
- Albumin affinity was measured alongside receptor affinity in the discovery series, so the albumin content of an assay buffer is part of the method record for this analogue [1]
- Storage
- Lyophilized at −20 °C, dark and dry; reconstituted aliquots kept cold and used promptly
Open questions
- The cited work characterizes the analogue as prepared by its originators; none of it reports an analytical identity check that would distinguish this acylated analogue from a related one in a supplied lot.
- Whether the c-Fos and transcript pattern reported in rat brain areas extends to other species is not established in the cited work.
- The rodent brain study names rats only for the transcriptomic analysis of microdissected brain areas, and does not name the species for the brain access mapping, the c-Fos immunolabeling or the behavioural measures.
- The two rodent atherosclerosis studies used different genetic backgrounds and different challenges, so the cited work does not establish which model the observation depends on.
Most of the published literature on this analogue is clinical and concerns a finished formulation; it is out of scope for a research material profile.
Lot records
Check the record for the exact material you order. A published paper and a batch certificate answer different questions.
No published lot is available for this exact compound name.
Read a certificate of analysis ↗References
- Lau J, Bloch P, Schäffer L, et al. Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide. Journal of medicinal chemistry. 2015.
- Zhang X, Belousoff MJ, Liang YL, et al. Structure and dynamics of semaglutide- and taspoglutide-bound GLP-1R-Gs complexes. Cell reports. 2021.
- Gabery S, Salinas CG, Paulsen SJ, et al. Semaglutide lowers body weight in rodents via distributed neural pathways. JCI insight. 2020.
- McLean BA, Wong CK, Kaur KD, et al. Differential importance of endothelial and hematopoietic cell GLP-1Rs for cardiometabolic versus hepatic actions of semaglutide. JCI insight. 2021.
- Li Q, Tuo X, Li B, et al. Semaglutide attenuates excessive exercise-induced myocardial injury through inhibiting oxidative stress and inflammation in rats. Life sciences. 2020.
- Rakipovski G, Rolin B, Nøhr J, et al. The GLP-1 Analogs Liraglutide and Semaglutide Reduce Atherosclerosis in ApoE-/- and LDLr-/- Mice by a Mechanism That Includes Inflammatory Pathways. JACC. Basic to translational science. 2018.
Publication records fetched from PubMed on 2026-09-20. Profile text reviewed 2026-09-20.