Peptide Bonds and Sequences

What a peptide bond is

A peptide bond is the chemical link between two amino acids. It forms in a reaction that removes a molecule of water as it joins the amino group of one amino acid to the carboxyl group of its neighbor. [1] Reviews also call this link an amide bond. [2]

Repeating that link builds a chain. Picture a row of beads on a string: each bead is an amino acid, and the string is the series of peptide bonds. The beads themselves are called residues once they are part of a chain. [3]

What a sequence is

The sequence is the order of the amino acids along the chain. For a protein, this linear order is called the primary structure, and it drives how the chain folds. [1] Short peptides generally lack the stable folded structure larger proteins have. [4]

Sequence is the main way a peptide is identified. A few real examples from the literature:

• GHK is a three-amino-acid peptide, written out as glycyl-L-histidyl-L-lysine, which names its three units in order. [5]


• GnRH, a hormone made by neurons in the hypothalamus, has 10 amino acids. [4]


• GLP-1 has 37 amino acids and has a very short half-life in the body. [4]

Why small changes make a different molecule

Because the order and identity of each unit define the molecule, changing even one position can create a different compound. Chemists do this deliberately when designing medicines. Examples from reviews:

• Swapping an amino acid. Replacing L-amino acids (the form found in natural peptides) with their mirror-image D-forms can improve a peptide's stability against breakdown by enzymes. [2]
• Adding a fatty acid. Liraglutide is described as a chemically synthesized analogue of human GLP-1 made by attaching a C-16 fatty acid, through a glutamic acid spacer, to the lysine at position 26. [4]
• Using unnatural amino acids. The FDA notes that GHRP-2 contains an unnatural amino acid, which adds to the complexity of characterizing it. [6]
• Changing the ends. Peptide ends can also be modified, for example by N-terminal acetylation. [2]

The FDA draft guidance lists some structural alterations used in peptide drug development: cyclization (closing the chain into a ring), pseudo-peptide bonds, unnatural amino acids and conjugations such as PEGylation. [7] Details are on lipidation, PEGylation and cyclization.

Why bonds matter for stability

Peptide bonds can be cut by enzymes. Digestive enzymes such as pepsin, trypsin and chymotrypsin cleave them and can inactivate the molecule. [3] Amide bonds in natural peptides can be easily hydrolyzed or destroyed by enzymes in the body. [4] This is a core reason natural peptides tend to act for a short time. For example, unmodified insulin has a reported half-life of less than 5 minutes. [3] See half-life and clearance.

Reading names and sequences carefully

A name is not a sequence, and two products sold under similar names are not necessarily the same molecule. Confirming exact identity needs the sequence and chemical modifications from a reliable source. This library only states an exact sequence where we could read it in a source. For naming problems, see research peptide naming and identity problems. Short definitions are in the peptide glossary.