Definition
Lipidation, or acylation with a fatty acid, attaches a lipid chain to a peptide, most often through a lysine side chain and sometimes via a spacer. In incretin research, the main purpose is reversible binding to serum albumin, which circulates for weeks; the albumin-bound fraction is protected from renal filtration and enzymatic cleavage, greatly extending half-life. Liraglutide carries a C16 palmitic acid chain, while semaglutide and tirzepatide carry C18 or C20 diacids attached through hydrophilic linkers. Cagrilintide is a lipidated amylin analogue. Lipidation increases hydrophobicity, which lengthens HPLC retention time and can promote self-association in solution. It is distinct from natural lipid modifications such as the octanoyl group on ghrelin.