Liraglutide (GLP-1 Analogue)

Overview

Liraglutide is an acylated analogue of glucagon-like peptide-1, and the compound that established acylation as a workable strategy for extending peptide half-life. Everything in the GLP family documented here descends from it, directly or in approach.

We do not stock it. It is included because the semaglutide page describes three modifications without a baseline to compare them against, and this is the baseline.

Chemical identity

• CAS number: 204656-20-2
• Molecular formula: C₁₇₂H₂₆₅N₄₃O₅₁
• Molecular weight: approximately 3751 g/mol
• Classification: GLP-1 receptor agonist, acylated peptide analogue
• Length: 31 residues plus the acylation

At 3,751 g/mol it is past the size where a structure diagram remains readable. As with semaglutide, the formula contains no sulfur.

The problem, and the first good answer

Native GLP-1 lasts about two minutes in circulation, cleaved by DPP-4 and cleared renally. That is fine for a hormone signalling that a meal has arrived and useless for anything requiring sustained presence.

Early GLP-1 analogues addressed degradation but not clearance, and required frequent administration. Liraglutide was the first to solve both at once, using a strategy that has since become standard:

• Position 34: lysine to arginine. Not a stability change but a chemical one — it removes a second lysine so that the acylation attaches at one defined site rather than either of two.
• Position 26: acylation with a C16 fatty acid (palmitic acid), attached through a glutamic acid spacer. The chain binds reversibly to albumin in circulation, and bound peptide is shielded from both enzymatic degradation and renal filtration.

That took the half-life from about two minutes to roughly thirteen hours — sufficient for once-daily administration, and a large enough improvement to make the whole class practical.

Note what is not in that list: liraglutide retains the native alanine at position 8, the residue DPP-4 attacks. It has no substitution protecting that site. Its resistance comes indirectly, from albumin binding making the peptide unavailable to the enzyme rather than from making the peptide unrecognisable to it.

What semaglutide changed

This comparison is the reason to read the two pages together. Semaglutide makes three changes to liraglutide’s design, and each addresses a specific limitation:

• Aib at position 8. The non-standard amino acid that blocks DPP-4 cleavage directly, rather than relying on albumin to hide the site. This is the modification liraglutide lacks.
• A C18 diacid instead of a C16 monoacid. A longer chain with a carboxyl group at each end binds albumin more tightly than palmitic acid does.
• A longer spacer. Additional linker units between peptide and fatty acid, giving the chain more freedom to reach its binding pocket without straining the peptide.

The result is 363 g/mol of added mass and roughly a thirteenfold increase in duration — from thirteen hours to about a week, from daily administration to weekly.

This is a good illustration of how incremental molecular engineering actually works. No single change is dramatic. Together they turn a workable compound into a considerably better one, and the improvement is legible modification by modification precisely because both molecules are documented.

Mechanism of action

Liraglutide agonises the GLP-1 receptor, a G-protein coupled receptor expressed in pancreatic beta cells, the gastrointestinal tract and appetite-regulating regions of the brain, signalling through cyclic AMP.

Its effects on insulin secretion are glucose-dependent, a property intrinsic to GLP-1 biology rather than engineered into the analogue: the receptor amplifies insulin release when glucose is elevated and does comparatively little when it is not.

The family line

With this compound documented, the GLP-related compounds in this library form a legible sequence of development:

• Liraglutide — GLP-1 alone. C16 acylation. Daily.
• Semaglutide — GLP-1 alone. Aib8, C18 diacid, longer spacer. Weekly.
• Tirzepatide — GIP and GLP-1, built on a GIP backbone. Weekly.
• Retatrutide — GIP, GLP-1 and glucagon. Investigational.
• Cagrilintide — a different hormone entirely, amylin, using the same acylation strategy and studied alongside semaglutide.

The first two steps are about duration; the later ones are about receptor combination. Once weekly dosing was solved, the field’s attention moved from making one signal last to combining several — which is the shape of the whole story in one list.

Regulatory status

Liraglutide is an approved prescription medicine in the United States, the European Union and elsewhere, marketed under separate brand names for type 2 diabetes and for weight management at different doses.

As with the other approved compounds documented here, material supplied for laboratory research is not a pharmaceutical product, has not been manufactured or released under the controls governing an approved medicine, and is not a substitute for one. Anyone whose interest is medical should be speaking to a clinician.

Reported observations

Gastrointestinal effects predominate in the trial literature — nausea, vomiting, diarrhoea, constipation — dose-related and most pronounced during escalation, the pattern shared across this class. Gallbladder-related events and pancreatitis appear at lower frequency, and warnings derived from rodent studies regarding thyroid C-cell tumours apply as they do to the other GLP-1 analogues.

These come from large randomised trials with systematic adverse event collection rather than from small preclinical studies.

Handling and storage

• Surface activity from the acylation. The fatty acid chain promotes adsorption onto container walls and foaming on agitation. Do not shake.
• No oxidation-prone residues — no sulfur in the formula means no methionine or cysteine.
• Lyophilised storage: sealed, refrigerated, protected from light; freeze for long-term storage.
• Reconstitution: add diluent slowly down the vial wall and allow to dissolve undisturbed.

Purity and analytical verification

The acylation is the critical feature and the thing worth confirming, exactly as for semaglutide. A batch in which acylation failed is missing a large, well-defined mass, and an unacylated backbone would have a half-life of minutes rather than hours — a functionally different compound.

There is one consideration specific to liraglutide. Its C16 monoacid is smaller than semaglutide’s C18 diacid, so the mass difference between correctly acylated and unacylated material is correspondingly smaller. It remains readily detectable, but it is a reminder of the principle set out on the tesamorelin page: how easily a modification can be verified depends on its size relative to the molecule carrying it.

Thirty-one coupling steps also generate a substantial deletion-sequence population, so HPLC purity is doing real work.

References

• Knudsen LB, Nielsen PF, Huusfeldt PO, et al. Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration. Journal of Medicinal Chemistry, 2000. PMID 10794683
• Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. New England Journal of Medicine, 2015. PMID 26132939
• Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. New England Journal of Medicine, 2016. PMID 27295427

Summary

Liraglutide is an acylated GLP-1 receptor agonist, CAS 204656-20-2, molecular formula C₁₇₂H₂₆₅N₄₃O₅₁, molecular weight approximately 3,751 g/mol. An arginine substitution at position 34 directs acylation to a single site, and a C16 palmitic acid chain on position 26 gives reversible albumin binding — taking the half-life from about two minutes to roughly thirteen hours and making once-daily administration possible. It retains the native alanine at position 8, so its DPP-4 resistance is indirect. Semaglutide’s three further changes — Aib8, a C18 diacid, and a longer spacer — added 363 g/mol and roughly thirteenfold more duration. It is an approved prescription medicine. We do not stock it.

This page is provided for research reference. Compounds described in this library are for laboratory research use only, are not drugs, foods or cosmetics, and may not be used for any purpose other than in vitro or non-human laboratory research. References to clinical studies describe the published scientific literature and are not guidance for use.