Peptide bond

A peptide bond is an amide bond between two amino acids. The carboxyl group of one amino acid reacts with the amino group of the next, a molecule of water is released, and the two are joined. Repeat that and you get a chain with a direction: a free amino group at one end, the N-terminus, and a free carboxyl group at the other, the C-terminus. Sequences are always written from N to C.

A short chain is a peptide. A long folded chain is a protein. There is no official cut-off, but chains of up to about 50 amino acids are usually called peptides. Semaglutide's backbone is 31 amino acids, the length of GLP-1(7-37), and tirzepatide is 39. The what are peptides page has the wider picture.

Why the bond matters for drugs

The bond is stable on a shelf in a dry vial, which is why lyophilised peptides keep well, but the body has enzymes, called proteases and peptidases, whose job is to cut it. Each enzyme recognises particular sequences. DPP-4, for example, clips the first two amino acids off GLP-1, and that single cut is enough to inactivate it. The labels for liraglutide state that endogenous GLP-1 lasts 1.5 to 2 minutes for this reason.

Drug designers work around the cuts. The Wegovy label describes three changes to semaglutide:

• Position 8 is modified to resist DPP-4. Native GLP-1 has alanine there; semaglutide uses aminoisobutyric acid (Aib), which the enzyme does not cut.
• Position 26, a lysine, carries a spacer and a C18 fatty diacid. That chain binds albumin in the blood, which slows clearance and shields the backbone.
• Position 34 is changed so only one fatty acid attaches.

Tirzepatide uses Aib at positions 2 and 13 and a C20 fatty diacid on the lysine at position 20, according to its label. Liraglutide uses a C16 fatty acid on lysine 26.

How the body finally breaks them down

Even an engineered peptide is eventually cut. The Wegovy label states that semaglutide is eliminated mainly by proteolytic cleavage of the peptide backbone and beta-oxidation of the fatty acid side chain. The engineering does not prevent this; it slows it down, from minutes to about a week.

How the bonds are made

In the body, ribosomes build peptide bonds by reading a genetic template. Drug makers use one of two routes. Biological production puts the gene into yeast or bacteria: the Wegovy label says semaglutide's peptide backbone is produced by yeast fermentation, and the Saxenda label says liraglutide's precursor is made in Saccharomyces cerevisiae. Chemical solid-phase synthesis instead adds one amino acid at a time to a chain anchored on resin beads. Most research peptides are made the second way.

Why this matters outside the clinic

Peptide bonds are also where things go wrong in a vial. Heat, moisture and repeated freeze-thaw can break bonds or rearrange amino acids, producing fragments that an HPLC test shows as impurity peaks. Synthesis can also skip or double an amino acid, leaving a chain that is one link short or one link long. Those are the related substances that purity testing looks for. The storage guide covers temperature.

The app's vial tracker records when each vial was reconstituted and how many doses remain, which is the practical side of keeping those bonds intact.

Related terms: amino acid sequence, lyophilised, purity testing, receptor agonist. Back to the glossary.