Peptide Nomenclature: Reading Sequences, Modifications and Names

A peptide spec sheet is dense with shorthand, and every symbol is load-bearing. Two peptides differing by a single "Ac-" prefix can differ by an order of magnitude in half-life.

The backbone: sequences

Peptides are written N-terminus to C-terminus, left to right. Always. This convention is universal and never varies.

Two coding systems coexist:

Three-letter codes are unambiguous and standard on spec sheets: `Gly-Glu-Pro-Pro-Pro-Gly-Lys`

One-letter codes are compact and standard in databases: `GEPPPGK`

Both describe the same molecule. The three-letter form is preferred where modifications are involved, because it leaves room for them.

N-terminal modifications

The free N-terminus is a primary amine, positively charged at physiological pH and a target for aminopeptidases. Modifying it changes both.

Ac- — acetylation. Caps the amine with an acetyl group, removing the positive charge and blocking aminopeptidase attack. Adds 42 Da. Extremely common: TB-500's sequence begins `Ac-Ser-Asp-Lys-`.

Pyr- or pGlu- — pyroglutamate. A cyclised N-terminal glutamine, occurring both naturally and as a synthesis artefact.

Fmoc- or Boc- — protecting groups from solid-phase synthesis. Their presence in a final product means incomplete deprotection, which is a defect rather than a design choice.

C-terminal modifications

-NH2 — C-terminal amidation. Replaces the terminal carboxylic acid with an amide. This is not cosmetic: many endogenous peptide hormones are amidated, and the amide is frequently required for receptor binding. Ipamorelin is `Aib-His-D-2-Nal-D-Phe-Lys-NH2`, and the amide matters.

-OH — the free acid. Often written explicitly to make clear the peptide is not amidated.

D-amino acids

Biological amino acids are almost exclusively L-enantiomers. Substituting a D-enantiomer produces a molecule with identical mass and near-identical chromatographic behaviour but a different three-dimensional shape.

Written as `D-Phe`, `D-Ala`, `D-2-Nal`.

The purpose is usually protease resistance: peptidases evolved to cleave L-peptides and often cannot process a D-residue at or near the scissile bond. The cost is that receptor binding may also change, so D-substitution is a deliberate structure-activity trade rather than a free upgrade.

This is also why chiral purity deserves its own line on a COA. Racemisation during synthesis produces a contaminant that HPLC and MS will both cheerfully report as pure, correct material.

Unnatural residues

Beyond the canonical twenty:

Aib — α-aminoisobutyric acid. A doubly methylated alanine that strongly favours helical conformations and resists proteolysis. It opens both Ipamorelin and tirzepatide's modified positions.

Nal — naphthylalanine. A bulky aromatic side chain, often used to enhance receptor affinity. `2-Nal` and `1-Nal` denote the attachment position on the naphthalene ring.

Cha — cyclohexylalanine, a saturated phenylalanine analogue.

Orn — ornithine, one methylene shorter than lysine.

Sar — sarcosine (N-methylglycine), which removes a backbone hydrogen bond donor.

Conjugations and half-life extension

PEG- — polyethylene glycol attached covalently. Increases hydrodynamic radius, slows renal clearance, reduces immunogenicity. Usually specified with the polymer mass: PEG5000.

Fatty acid acylation — attaching a C16 or C18 chain, often via a γ-Glu spacer, so the peptide binds serum albumin reversibly. This is the mechanism behind semaglutide's extended half-life, and the reason its formula runs to 187 carbons.

DAC — drug affinity complex. A maleimido propionic acid linker that forms a covalent bond with serum albumin cysteine-34. CJC-1295 with DAC and CJC-1295 without DAC are pharmacologically very different molecules despite sharing a core sequence.

Disulfides and cyclisation

Cyclo(...) — head-to-tail or side-chain cyclisation, conferring conformational rigidity and protease resistance. PT-141 is cyclic.

Disulfide bridges are written as connectivity: `Cys3-Cys14` indicates a bond between the cysteines at positions 3 and 14. A peptide with the right mass but the wrong disulfide pairing is a different molecule with the same formula — which is why disulfide mapping exists as a separate assay.

Salt forms

TFA salt — trifluoroacetate, the default from RP-HPLC purification with TFA in the mobile phase. Cheap and standard, but TFA is cytotoxic at surprisingly modest concentrations and interferes with some cell assays.

Acetate salt — produced by salt exchange after purification. Preferred for cell-based work.

HCl salt — another exchange option.

The salt form affects net peptide content. A TFA salt of a lysine-rich peptide can be 20–25% counter-ion by mass, so the same "10 mg" vial delivers meaningfully less peptide than an acetate salt of the same compound.

Putting it together

`Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-Ile-Glu-Lys-Phe-Asp-Lys-Ser-Lys-Leu-Lys-Lys-Thr`

Reading this: acetylated N-terminus (protease-protected), free C-terminal acid, twenty residues, all L-configuration, one methionine at position 6 (oxidation-prone — store cold and dark), heavily lysine-rich (so expect substantial counter-ion mass in a TFA salt).

That is four handling decisions, read directly off the sequence line.

For laboratory research use only.