The side chain of semaglutide, often referred to as the "semaglutide side chain" or "semaglutide linker," is a precisely designed chemical modification responsible for the ultra-long-acting property that allows semaglutide to be administered just once a week.
Chemical Structure and Function of the Side Chain
Semaglutide is a product of multi-point chemical modification of the human GLP-1 peptide. Its key feature is a special side chain attached to the lysine residue at position 26 (K26) of the peptide backbone.
Complete Chemical Composition of the Side Chain (connected from inner to outer):
| Connection Point & Composition | Functional Role |
|---|---|
| Attachment Point: Lysine at position 26 (K26) | Ensures accurate linkage of the side chain. |
| Spacer: Two consecutive "AEEA" units (8-amino-3,6-dioxaoctanoic acid) | Provides a flexible, hydrophilic linkage, minimizing interference with the biological activity of the parent peptide. |
| Linker: A glutamic acid molecule | Acts as a bridge connecting the spacer to the fatty acid chain. |
| Core Functional Group: A C18 fatty diacid side chain (octadecanedioic acid) | Core Function: Binds strongly to albumin in the bloodstream, creating a "depot effect" crucial for the long duration of action. |
In summary, this ingeniously designed side chain extends the half-life of the drug from just minutes (for native human GLP-1) to approximately one week (168 hours). It achieves this by increasing resistance to metabolic enzymes through steric hindrance and utilizing albumin binding. This transformation enables the shift from daily injections to once-weekly administration.
As a Synthetic Intermediate
In pharmaceutical manufacturing, the "semaglutide side chain" itself is a critical synthetic intermediate (CAS Number: 1118767-16-0). Its purity and quality directly impact the efficacy and safety of the final drug product and is primarily supplied to drug research, development, and production institutions.
