acetyl tetrapeptide-5
Ac-beta-Ala-His-Ser-His-OH, N-acetyl-beta-alanyl-L-histidyl-L-seryl-L-histidine, Ac-bAla-His-Ser-His
Acetyl tetrapeptide-5 is a synthetic four-residue peptide whose first two residues, beta-alanine and histidine, are exactly the dipeptide carnosine. It is used mainly in eye-area cosmetics on the claim that it reduces puffiness by inhibiting angiotensin-converting enzyme and by limiting glycation of dermal proteins. One independent laboratory has measured ACE activity in fibroblasts exposed to the peptide; there is no published clinical trial.
Mechanism
Two distinct pharmacophores sit in this molecule. The N-terminal beta-alanyl-histidine unit is carnosine, an endogenous dipeptide with a substantial literature as a carbonyl scavenger, transition-metal chelator and inhibitor of advanced glycation end-product formation. Carnosine reacts with reactive carbonyl species such as methylglyoxal before they cross-link long-lived proteins including dermal collagen, and buffers metal-catalysed oxidative chemistry through the imidazole ring. Extending carnosine to a tetrapeptide with a second histidine and a serine preserves that imidazole chemistry, while acetylation removes the free amine that would otherwise be the site of aminopeptidase cleavage.
The second claimed action is inhibition of angiotensin-converting enzyme. Histidine- and proline-rich short peptides are a recognised class of ACE inhibitors in the food-peptide literature, and the cosmetic rationale is that local ACE inhibition in periorbital tissue reduces capillary permeability and therefore fluid accumulation under the thin lower-eyelid skin. Wu and colleagues, working independently of the ingredient supplier, tested acetyl tetrapeptide-5 in human skin fibroblasts and identified 100 micrograms per millilitre as its optimal concentration for angiotensin-converting enzyme 1 activity. What has not been shown is anything downstream: that a topically applied peptide reaches periorbital dermis and vasculature, that local ACE inhibition there reduces oedema, or that any of this produces visible change.
What the research shows
Wu and colleagues screened five cosmeceutical peptides in human skin fibroblasts under hydrogen-peroxide-induced premature senescence. Each peptide was assigned an optimal concentration for a different endpoint; for acetyl tetrapeptide-5 that endpoint was angiotensin-converting enzyme 1 activity, optimal at 100 micrograms per millilitre. It is worth being precise here, because the point is easy to overstate: the study did not rank the five peptides against one another for ACE inhibition, so acetyl tetrapeptide-5 cannot be described as the 'strongest' ACE inhibitor of the set. A four-peptide mixture containing it (with carnosine, hexapeptide-11 and acetyl hexapeptide-3) significantly reduced intracellular malondialdehyde and hydroxyl free radical content and increased hydroxyproline, elastin, superoxide dismutase and glutathione peroxidase.
The carnosine literature underpinning the anti-glycation claim is strong in its own right. Boldyrev, Aldini and Derave's review in Physiological Reviews sets out carnosine's carbonyl-scavenging, metal-chelating and pH-buffering roles; Hipkiss has argued specifically for carnosine's relevance to glycation and ageing; and Guiotto's review covers the chemistry of carnosine and its derivatives as antioxidants. The beta-alanyl-histidine half of this molecule is doing chemistry that is well characterised. Extrapolating from that to a clinical effect on eye bags is not supported. That remains unstudied in the open literature.
Evidence assessment
Preclinical only
The biochemical claim has partial independent support in cell culture, and the carnosine anti-glycation chemistry is extensively documented for the parent dipeptide. But there is no published human study of the ingredient: no controlled trial of periorbital oedema, no imaging or volumetric endpoint, no independent penetration study. Supplier-reported reductions in eye-bag volume have not been peer reviewed. A PubMed phrase search returns exactly one record, the Wu 2021 in vitro screen. In vitro support with no clinical data is the definition of preclinical.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Protective and Anti-Aging Effects of 5 Cosmeceutical Peptide Mixtures on Hydrogen Peroxide-Induced Premature Senescence in Human Skin Fibroblasts Preclinical only
For acetyl tetrapeptide-5 the optimal concentration was 100 micrograms per millilitre for angiotensin-converting enzyme 1 activity. A four-peptide mixture containing it reduced intracellular malondialdehyde and hydroxyl free radicals and increased hydroxyproline, elastin and antioxidant enzyme activity.
Physiology and pathophysiology of carnosine Preclinical only
Sets out carnosine's carbonyl-scavenging, metal-chelating, pH-buffering and antiglycating chemistry, the biochemistry of the beta-alanyl-histidine unit at the N-terminus of this peptide.
Glycation, ageing and carnosine: are carnivorous diets beneficial? Preclinical only
Argues the case for carnosine as an inhibitor of advanced glycation end-product formation relevant to tissue ageing.
Carnosine and carnosine-related antioxidants: a review Preclinical only
Reviews the antioxidant and antiglycating chemistry of carnosine and structurally extended derivatives, the class to which this tetrapeptide belongs.
Safety
No safety signal has been reported. Carnosine itself is an endogenous dipeptide present in human muscle and brain at millimolar concentrations and consumed in the diet, which gives some reassurance about the N-terminal fragment. The intact peptide is used at low concentrations in leave-on eye products. Because it is applied close to the eye, the main practical caution is ocular irritation from the finished formulation rather than from the peptide; products should be kept out of the eye. There are no reproductive or systemic toxicity data and no human pregnancy or lactation data. This is a topical cosmetic ingredient and has not been evaluated for injection, including periocular injection of any kind.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Permitted as a cosmetic ingredient under the UK Cosmetics Regulation (retained Regulation (EC) No 1223/2009); not listed in any prohibited or restricted annex. A Cosmetic Product Safety Report and responsible person are required, with particular attention to eye-area exposure. No MHRA medicines authorisation. |
| United States | Not an FDA-approved drug and not covered by an OTC drug monograph; marketed as a cosmetic ingredient under the FD&C Act as amended by the Modernization of Cosmetics Regulation Act 2022. Claims that a product reduces eyelid oedema could be read as drug claims depending on wording. |
| WADA (sport) | Not named on the WADA Prohibited List. Topical cosmetic use raises no anti-doping issue. |
Questions
Directly. Its first two residues are beta-alanine and histidine, which together are carnosine. The molecule is essentially carnosine extended by serine and a second histidine, with the N-terminus acetylated to block enzymatic degradation.
No published human trial has tested that. There is independent cell-culture evidence that the peptide has measurable angiotensin-converting enzyme activity in fibroblasts, which is the first step in the proposed mechanism, but nothing published shows that topical application reduces periorbital oedema in people.
On carnosine chemistry. Carnosine scavenges reactive carbonyl species such as methylglyoxal and chelates transition metals, both of which limit advanced glycation end-product formation, and this is well documented for carnosine itself. Whether the tetrapeptide retains that activity in skin at cosmetic concentrations has not been demonstrated.
No safety signal has been reported for the peptide, and its carnosine fragment is an endogenous compound present at high concentrations in human tissue. The practical risk in an eye product usually comes from the rest of the formulation. Keep it out of the eye itself, and note that no injectable use has been evaluated.