Lipidation
The attachment of a fatty acid chain to a peptide molecule, typically to enable albumin binding and thereby extend the peptide's half-life in circulation. Semaglutide and liraglutide both use lipidation as their primary half-life extension strategy.
Technical Context
Lipidation exploits the reversible binding of fatty acid-modified peptides to albumin in the bloodstream. When the peptide-albumin complex circulates, the large size of albumin (approximately 67 kDa) prevents renal filtration, and the bound state shields the peptide from proteolytic enzymes. Semaglutide uses a C-18 fatty diacid attached via a mini-PEG linker at Lys26 to achieve albumin binding, extending its half-life to approximately 165 hours (enabling weekly dosing). Liraglutide uses a C-16 fatty acid (palmitic acid) at Lys26, achieving a half-life of approximately 13 hours (daily dosing). This albumin-binding lipidation platform has become a key technology in long-acting peptide drug development.