Pentapeptide-18

What Is Pentapeptide-18?

Pentapeptide-18 is a synthetic linear peptide of five amino acids, tyrosine, D-alanine, glycine, phenylalanine and leucine, used as an anti-wrinkle ingredient in cosmetics. Its structure is the same as [D-Ala2]leucine-enkephalin, an analog of the endogenous opioid pentapeptide leucine-enkephalin.

Researchers describe pentapeptide-18 as a commercial anti-wrinkle peptide.^[1] The authors of a 2026 computational study characterize it as a neuromodulatory peptide that is reported to reduce wrinkle formation by inhibiting neurotransmitter release, and to improve skin hydration, elasticity and texture.^[2] These descriptions summarize prior claims; the underlying efficacy data are not presented in the abstracts reviewed here.

The indexed literature on pentapeptide-18 is small. It includes two 2024 studies of lipid nanoparticles combining the peptide with retinol,^[3][4] a 2020 study of a D-tyrosine-modified version,^[1] and the 2026 spectroscopic and computational study.^[2]

Chemical Structure and Molecular Identity

Pentapeptide-18 is L-tyrosyl-D-alanylglycyl-L-phenylalanyl-L-leucine (Tyr-D-Ala-Gly-Phe-Leu), a pentapeptide with a free N-terminal amine and a free C-terminal carboxylic acid. PubChem (CID 10099522) lists the molecular formula C29H39N5O7 and a molecular weight of 569.6 g/mol.

The defining feature is the D-alanine at position 2. Natural leucine-enkephalin has the sequence Tyr-Gly-Gly-Phe-Leu; pentapeptide-18 differs only by replacing the second glycine with D-alanine. Because it contains a D-amino acid, it cannot be represented by a standard all-L one-letter sequence, although it is sometimes written H-Y(dA)GFL-OH.

Key identifiers

• CAS number: 64963-01-5
• InChIKey: ZHUJMSMQIPIPTF-JMBSJVKXSA-N
• UNII: PO4D55T1IG
• Other registry numbers: NSC 374895; EINECS 265-291-0
• Synonyms: [D-Ala2]leucine-enkephalin, (D-Ala2)-Leu-enkephalin, H-Tyr-D-Ala-Gly-Phe-Leu-OH

A 2026 study characterized the molecule’s structure in detail. Researchers optimized its geometry and electronic properties with density functional theory using the 6-31++G(d,p) basis set, analyzed frontier molecular orbitals (HOMO-LUMO) and the molecular electrostatic potential, and assigned theoretical vibrational frequencies that were then compared with FTIR, ATR-FTIR and Raman spectra.^[2]

Research History and Development

Pentapeptide-18 entered the peer-reviewed literature mainly as a cosmetic ingredient to be formulated, modified or modeled, not as a subject of mechanistic biology. The available studies date from 2020 onward.

In 2020, researchers used pentapeptide-18 as a test case for adding a terminal D-tyrosine to short cosmetic peptides. The goal was to add an anti-melanogenic effect to a peptide’s existing activity, and the same approach was applied to the peptides GEKG and GHK.^[1]

In 2024, two studies paired pentapeptide-18 with retinol in solid lipid nanoparticles. The first optimized and characterized the nanoparticle dispersion as a cosmetic raw material,^[3] and the second incorporated it into semi-solid formulations and tested them in volunteers.^[4] The authors framed lipid nanocarriers as a way to use the properties of pentapeptide-18 and retinol while reducing the undesirable effects of retinoid therapy.^[4]

Most recently, a 2026 study combined spectroscopy with molecular docking, molecular dynamics and ADMET (absorption, distribution, metabolism, excretion and toxicity) predictions to assess pentapeptide-18 as an anti-aging candidate.^[2]

Mechanisms Studied in Research

Proposed mechanisms for pentapeptide-18 center on inhibition of neurotransmitter release and, in computational work, interactions with skin-aging signaling proteins; direct experimental confirmation is not described in the abstracts. The neuromodulatory mechanism is presented as background in the 2026 study rather than tested there.^[2]

Computational target modeling

The 2026 study used molecular docking and molecular dynamics simulations to examine how pentapeptide-18 might bind targets implicated in skin aging, including TGF-beta, TNF-alpha, MAPK, PI3K/AKT and NF-kappaB. The authors chose these pathways because they regulate inflammation, oxidative stress and extracellular matrix remodeling.^[2] Binding results are not reported in the available abstract, and docking predictions do not demonstrate activity in cells or skin.

Anti-melanogenic modification

A separate line of work added a mechanism rather than studying an existing one. D-tyrosine inhibits tyrosinase activity, and attaching a terminal D-tyrosine to pentapeptide-18 gave the modified peptide the ability to reduce tyrosinase activity and melanin content in pigment cells.^[1] This effect belongs to the D-tyrosine-modified peptide, not to unmodified pentapeptide-18.

Receptor pharmacology

Although pentapeptide-18 shares its structure with an enkephalin analog, the cosmetic studies reviewed here do not report opioid-receptor binding or signaling measurements for it.

Key Findings From Published Studies

Published findings on pentapeptide-18 cover nanoparticle stability, a volunteer study of a combined retinol formulation, and cell and 3D skin model results for a D-tyrosine-modified variant. No study isolates the effect of unmodified pentapeptide-18 in human skin.

Retinol and pentapeptide-18 lipid nanoparticles (formulation study)

Solid lipid nanoparticles were produced by high-shear homogenization in three versions: empty, retinol only, and retinol plus pentapeptide-18. After four weeks of storage at 25 °C, the optimized retinol and peptide dispersion had a mean particle size of 134.7 nm, a polydispersity index of 0.269 and a zeta potential of 42.7 mV, values the authors considered suitable for a cosmetic raw material.^[3]

Semi-solid formulations (volunteer study)

Creams enriched with retinol and pentapeptide-18-loaded lipid nanocarriers remained stable regardless of storage temperature, with 25 °C recommended. In volunteers, the products significantly reduced sebum secretion and decreased the number of facial wrinkles, and the lipid nanoparticles reduced the irritation usually associated with retinol.^[4] Because retinol was present, the results cannot be credited to the peptide alone.

D-tyrosine-modified pentapeptide-18 (cell and 3D skin models)

Adding a terminal D-tyrosine to pentapeptide-18 reduced melanin content and tyrosinase activity in human MNT-1 melanoma cells and primary melanocytes. The modified peptide also inhibited melanogenesis induced by alpha-melanocyte-stimulating hormone or UV irradiation in MNT-1 cells and reduced melanin synthesis in the epidermal basal layer of a 3D human skin model.^[1] When the same D-tyrosine addition was applied to the peptides GEKG and GHK, it conferred anti-melanogenic effects without altering their intrinsic activities.^[1]

Spectroscopic and computational profiling

The 2026 study confirmed calculated vibrational assignments against experimental FTIR, ATR-FTIR and Raman spectra and assessed pharmacokinetic and drug-likeness properties in silico.^[2]

Because pentapeptide-18 depends on a single D-alanine for its identity, researchers typically confirm identity and purity with HPLC and mass spectrometry certificates of analysis.

Because pentapeptide-18 depends on a single D-alanine for its identity, researchers typically confirm identity and purity with HPLC and mass spectrometry certificates of analysis.

Regulatory and Research Status

Pentapeptide-18 is not an FDA-approved drug. It is used as a cosmetic ingredient under the name pentapeptide-18 and has not been evaluated in drug-development clinical trials.

The published evidence is limited in scope. The only human data come from a formulation that also contained retinol,^[4] the anti-melanogenic findings apply to a modified peptide,^[1] and the 2026 work is largely computational.^[2] The neuromodulatory mechanism commonly attributed to the peptide is cited as background rather than demonstrated in the indexed abstracts.^[2]

Evidence at a glance

Open questions include direct measurement of its effect on neurotransmitter release in skin-relevant models, its skin penetration as an unformulated peptide, and controlled studies that separate its contribution from co-ingredients such as retinol.