How is argireline manufactured?

The argireline, or acetyl hexapeptide-8, is a biomimetic peptide used in topical application to target expression lines. Its unique feature is that it acts on the same biological mechanism as botulinum toxin but without injections. Structurally designed to mimic the N-terminal end of the SNAP-25 protein, the argireline interferes with the formation of the SNARE complex, a molecular assembly essential for the release of acetylcholine at neuromuscular synapses. By competing with SNAP-25, argireline disrupts the complex’s stability without altering its other components, which limits neurotransmitter release involved in facial muscle contraction.

This modulation of neuromuscular communication reduces the intensity of repetitive facial movements, notably responsible for forehead wrinkles, crow’s feet and glabellar lines. By reducing these micro-contractions, the argireline progressively attenuates the length and depth of existing wrinkles, while helping to delay the appearance of new expression lines. Its biomimetic action makes it a particularly interesting active ingredient for smoothing facial contours without resorting to invasive procedures.

Argireline is obtained by solid-phase peptide synthesis, a method developed by the chemist Robert Bruce Merrifield and awarded the Nobel Prize in Chemistry in 1984.

This technique has transformed peptide production by enabling extremely precise, reproducible and rapid construction of peptide chains while minimising material loss. The principle is to assemble the peptides step by step on an insoluble solid support, ideal for swiftly filtering and washing the product after each reaction, without complex, time-consuming intermediate purifications.

The synthesis begins with the activation of a solid resin which serves as a fixed support. This resin is functionalised to produce an amino resin, the anchoring point for the first peptide building block. Each amino acid used is protected on its reactive sites to prevent unwanted reactions and ensure the accuracy of the synthesis. The initial coupling step involves assembling L-arginine, protected on its guanidino group, and L-glutamine, protected on its side-chain amine, to form a stable first tripeptide.

The peptide chain is then extended sequentially: addition of L-methionine, L-glutamic acid (with its side-chain carboxyl function protected), and then N-acetyl-L-glutamic acid. This allows the precise argireline sequence to be built up progressively. In each cycle, the strategy relies on three repetitive steps: deprotection, neutralisation, and then coupling of the newly activated amino acid, which ensures steady growth of the peptide chain whilst minimising assembly errors.

Once the six amino acids have been assembled, the complete argireline peptide remains attached to the resin and protected. It is then released by cleavage, before being purified to obtain pure, stable argireline that conforms to the expected sequence. Solid-phase synthesis offers four key advantages: the capacity to perform all reactions within a single reactor, the elimination of intermediate purification steps, high yields owing to the use of amino acids in excess, and enhanced solvation that minimises aggregation of intermediates. These characteristics explain why this method has become the benchmark for argireline production.

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• ROTSZTEJN H. & al. The peptide argireline – The importance of local application on the skin, in the light of current knowledge. Letters in Drug Design & Discovery (2017).

• JIRANUSORNKUL S. & al. Molecular modeling elucidates the cellular mechanism of synaptotagmin-SNARE inhibition: A novel plausible route to anti-wrinkle activity of botox-like cosmetic active molecules. Molecular and Cellular Biochemistry (2018).