Semaglutide

Chemical Identity

Property	Value
Chemical Formula	C187H291N45O59
Molecular Weight	4113.58 g/mol
CAS Number	910463-68-2
IUPAC Name	Modified GLP-1(7-37) analog
Peptide Class	GLP-1 Receptor Agonist
Sequence Homology	Human GLP-1(7-37) with modifications

Structure

Semaglutide is a synthetic analog of human glucagon-like peptide-1 (GLP-1(7-37)) incorporating two critical modifications:

1. Aib at position 8: Replacement of alanine with alpha-amino isobutyric acid (Aib) confers resistance to dipeptidyl peptidase-4 (DPP-4) enzymatic cleavage, which normally inactivates native GLP-1.

2. C-18 fatty diacid at lysine-26: A linker comprising a miniPEG spacer connected to an octadecanedioic acid (C-18 fatty diacid) is conjugated to the epsilon-amino group of Lys26. This lipid moiety enables non-covalent, reversible binding to serum albumin.

Half-Life Extension Mechanism

Native GLP-1 has a plasma half-life of approximately 2 minutes due to DPP-4 degradation and renal clearance. Semaglutide achieves a half-life of approximately 165 hours (approximately 7 days) through two synergistic mechanisms:

• DPP-4 resistance from Aib substitution at position 8
• Albumin binding via the C-18 fatty acid moiety, reducing renal filtration and providing a circulating reservoir

These modifications enable once-weekly subcutaneous dosing for the injectable formulation and once-daily oral administration.

Clinical Applications

Semaglutide received FDA approval for type 2 diabetes (2017) and obesity (2021). It activates GLP-1 receptors on pancreatic beta cells to enhance glucose-dependent insulin secretion, suppresses glucagon secretion, delays gastric emptying, and promotes satiety via central nervous system pathways.

References

• Nauck, M.A., Meier, J.J., & Holst, J.J. (2024). Nature Medicine. DOI: 10.1038/s41591-023-02593-0