Aib (2-Aminoisobutyric Acid)
Aib, 2-aminoisobutyric acid, is an achiral non-natural residue with two methyl groups on its alpha carbon that locks a helix in place and blocks protease cleavage, most famously at position 8 of semaglutide.
2-Aminoisobutyric acid, abbreviated Aib, is alanine with a second methyl group on the alpha carbon, so the residue has no stereocentre and no D or L form. The geminal dimethyl group restricts the backbone angles it can adopt, so Aib strongly favours helices, and its bulk denies proteases the extended substrate geometry they need. It has no one-letter code and appears as [Aib] in a sequence block; its residue mass is 85 daltons, 14 more than alanine.
Native GLP-1 is cleaved by dipeptidyl peptidase-4 between histidine 7 and alanine 8, in numbering inherited from proglucagon, within about two minutes of release; semaglutide replaces that alanine with Aib, written Aib8 in hormone numbering even though it is the second residue of the drug and sits at position two in its sequence block. Tirzepatide carries Aib at positions 2 and 13 of its own 39-residue chain, and ipamorelin begins with Aib as its first residue.
The substitution is a trade. A helix-locking residue can raise receptor affinity when the bound conformation is helical, as it is for the GLP-1 receptor, and lower it when flexibility at that position is needed. An Aib-containing peptide is also a different molecule from the hormone, with its own pharmacology, and because Aib is not genetically encoded it comes only from chemical synthesis.
Two confusions recur. The GHRH analogues tesamorelin is related to, modified GRF(1-29) and CJC-1295, block the same DPP-4 attack at position two with D-alanine, not Aib, and a listing that calls them Aib-substituted is describing a different compound. The other is numbering: Aib8 and Aib2 can be the same atom in semaglutide under two conventions, and a sequence block should be read against the numbering it declares.