What are the key steps in liraglutide synthesis?

What are the key steps in liraglutide synthesis?

How is liraglutide made?

Liraglutide is a modified GLP-1 analog. Its synthesis begins with solid-phase peptide synthesis to assemble the 31-amino-acid backbone. The sequence is built sequentially on a resin support, starting from the C-terminus and proceeding toward the N-terminus. Each amino acid is added through repeated cycles of deprotection and coupling.

What reagents and coupling agents are used?

Coupling agents such as DIC, HOBt, or HBTU are used to link amino acids during the build process. The modified lysine at position 26 is protected with a Dde or ivDde group to allow selective later attachment of the palmitic acid side chain. Once the linear sequence is complete, the peptide is cleaved from the resin with a trifluoroacetic acid cocktail that removes most side-chain protections.

What happens after cleavage?

After cleavage, the linear peptide is purified by reverse-phase high-performance liquid chromatography. Purification removes deletion sequences, deletion products, and other impurities. Purified linear peptide is then subjected to folding conditions to形成 the secondary structure needed for activity.

What steps involve the fatty acid attachment?

The fatty acid attachment occurs either on-resin or in-solution after cleavage. The protective group on Lys26 is removed under mild conditions using hydrazine, then the palmitoyl group is coupled to the exposed epsilon-amino group of the lysine. Palmitic acid itself is usually pre-activated as a glutamic acid-γ-palmitoyl-γ-carboxy compound to create the side-chain link.

When does the disulfide bridge form?

The native GLP-1 peptide has no disulfide bridge. Liraglutide keeps the modified Lys26 with the palmitoyl side chain and maintains the single cysteine pair from the modified GLP-1 sequence. No disulfide bridge is required for liraglutide.

How does liraglutide differ from semaglutide in synthesis?

Liraglutide keeps the palmitoyl side chain attached through a glutamic acid spacer, while semaglutide uses an octadecanoic acid diacid with a pair of PEG links. Synthesis of semaglutide requires more complex side-chain assembly and longer purification steps.

What company owns the liraglutide synthesis patents?

Novo Nordisk owns the original patents covering liraglutide manufacturing methods. Many patents are scheduled to expire soon, allowing generic and biosimilar companies to develop alternative methods.