Non-natural amino acids in peptide analogues: Aib, Nle, Dmt and others
Last reviewed 2026-10-10 · Sable Peptides · Research use only
Sable research method explainer. Updated 2026-10-10. Research use only.
Short answer
Ribosomes build proteins from 20 standard amino acids, but solid-phase synthesis can use many more. Non-natural (non-proteinogenic) amino acids are built into peptide analogues to restrict conformation, remove oxidation-prone or protease-sensitive residues, or probe structure-activity relationships. Several Sable reference compounds contain them, so it helps to recognise the abbreviations.
Aib: 2-aminoisobutyric acid
Aib has two methyl groups on its alpha carbon instead of a hydrogen and a side chain. This strongly restricts the backbone and favours helical conformations. Karle and Balaram analysed crystal structures of Aib-containing peptides and showed how Aib promotes helix formation (Karle and Balaram, 1990). Because Aib is achiral and alpha,alpha-disubstituted, peptidases that need an alpha hydrogen do not recognise it well.
In the catalogue, Aib appears at position 8 of semaglutide, at positions 2 and 13 of tirzepatide, and at positions 2 and 20 of retatrutide. It is also the N-terminal residue of ipamorelin (Aib-His-D-2Nal-D-Phe-Lys-NH2).
Other examples on the reference pages
- Nle (norleucine) is an unbranched isomer of leucine. It is often used in place of methionine because it lacks the sulfur atom that is prone to oxidation. Melanotan II and PT-141 both start Ac-Nle.
- Dmt (2',6'-dimethyltyrosine) is a tyrosine with two extra ring methyls. It is the second residue of SS-31 (D-Arg-Dmt-Lys-Phe-NH2).
- 2Nal (2-naphthylalanine) is a bulky aromatic residue, used in ipamorelin as its D form.
- Alpha-methyl-leucine is leucine with an extra methyl on the alpha carbon. Like Aib, it constrains the backbone, and it appears at position 13 of retatrutide.
- 2-methyl-D-tryptophan, in hexarelin, is a methylated D-tryptophan.
What to watch for analytically
Mass. Each non-natural residue has its own residue mass, so the expected mass on a certificate must be calculated from the exact modified sequence. Database formulas, such as those PubChem gives on the /ref pages, already include them.
Notation. One-letter codes do not cover non-natural residues. PubChem line notations sometimes show them as X, as the cagrilintide /ref page notes. Three-letter or named notation, as used in WHO INN sequences, is clearer.
Comparisons. When two analogues differ only by a non-natural residue, for example native GnRH against a substituted analogue, check the sequence and formula on each /ref page before you compare anything else. A one-residue change can shift the expected mass, the HPLC retention time and the net charge at the same time, so a side-by-side check of all three is the quickest way to confirm you have the compound you expect.
Synthesis. Hindered residues such as Aib couple more slowly in solid-phase synthesis, so deletion sequences missing that residue are a typical impurity to look for in the HPLC trace (Jones, 2002).
At Sable
The /ref pages give each sequence with its non-natural residues named, along with PubChem or WHO INN identifiers where on file. Batch identity is checked against the expected mass, and certificates are available for every lot at /coa. Sable Peptides has been operating since 2019 and supplies every compound mentioned here as laboratory research material only. Nothing on this page is advice on use in people or animals, and no administration or medical-use information is provided.
Key terms
- Proteinogenic
- One of the standard amino acids that ribosomes build into proteins.
- Alpha,alpha-disubstituted
- An amino acid with two non-hydrogen groups on its alpha carbon, such as Aib.
- Structure-activity relationship (SAR)
- Systematically relating changes in structure to changes in a measured property.
- Residue mass
- The mass an amino acid contributes inside a chain, which is its free mass minus water.
- Deletion sequence
- A synthesis impurity missing one or more intended residues.
Common questions
What is Aib?
2-aminoisobutyric acid, an alpha,alpha-dimethyl amino acid that favours helical structure.
Why use norleucine instead of methionine?
Norleucine has a similar shape but no oxidisable sulfur atom.
Which Sable compounds contain Aib?
Examples include semaglutide, tirzepatide, retatrutide and ipamorelin.
Related explainers
- D-amino acid substitution in peptides
- Lipidation: fatty-acid chains on peptides, with semaglutide as a structural example
Related reference pages
Sources
- Karle IL, Balaram P. Structural characteristics of alpha-helical peptide molecules containing Aib residues. Biochemistry. 1990;29(29):6747-6756. https://doi.org/10.1021/bi00481a001
- Jones J. Amino Acid and Peptide Synthesis. Oxford Chemistry Primers. Oxford University Press; 2002. https://doi.org/10.1093/hesc/9780199257386.001.0001
- Lau J, et al. Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide. J Med Chem. 2015;58(18):7370-7380. https://doi.org/10.1021/acs.jmedchem.5b00726
Questions
What is Aib?
2-aminoisobutyric acid, an alpha,alpha-dimethyl amino acid that favours helical structure.
Why use norleucine instead of methionine?
Norleucine has a similar shape but no oxidisable sulfur atom.
Which Sable compounds contain Aib?
Examples include semaglutide, tirzepatide, retatrutide and ipamorelin.
Sources
CoA for every lot — request yours and we email it within 2 hours.
Research use only. Not for human or veterinary use. No health claims.