Pentapeptide-18 (Leuphasyl) — The Enkephalin-Mimetic Anti-Wrinkle Peptide

A bioactive pentapeptide (H-Tyr-D-Ala-Gly-Phe-Leu-OH) that mimics endogenous enkephalin, binding to δ-opioid receptors on presynaptic nerve terminals. This triggers a G-protein-mediated cascade that closes calcium channels, reduces intracellular calcium concentration, and inhibits acetylcholine release — resulting in measurable muscle relaxation and visible reduction of expression lines. The D-Ala² modification enhances enzymatic stability and bioavailability. Clinically proven to reduce wrinkle depth by 11-24% in 28 days (monotherapy) and up to 47% when combined with Argireline (Acetyl Hexapeptide-8), targeting complementary steps in the neuromuscular signaling pathway. Also improves skin hydration, firmness, and radiance with an excellent safety profile. A premium non-invasive alternative to botulinum toxin injections, ideal for crow's feet, forehead lines, and frown lines.

Aliases: [D-Ala²]-leucine enkephalin, Leu-enkephalin

Amino acid sequence: H-Tyr-D-Ala-Gly-Phe-Leu-OH

Sequence abbreviation: Tyr-D-Ala-Gly-Phe-Leu

Molecular weight: 569.65 g/mol

Isoelectric point (pI): 9.36

Density: 1.257 g/cm³

Melting point: 160–163.5°C

Appearance: White to off-white powder

Solubility: Water-soluble

purity ≥95%–98% (HPLC)

Storage Conditions: Lyophilized powder should be stored sealed and protected from light at 2–8°C; for long-term storage, keep below –20°C.

Note: Pentapeptide-18 is a modified enkephalin in which the second amino acid, alanine, is replaced by D-conformation (D-Ala). This modification significantly enhances the peptide's resistance to enzymatic degradation, prolongs its half-life in the skin, and improves its biological activity.It is currently one of the most popular active peptides with neurotransmitter-inhibiting properties.

Core Efficacy

Inhibits acetylcholine release and reduces dynamic wrinkles (core efficacy)

The mechanism of action of pentapeptide-18 differs from that of argireline (acetylated hexapeptide-8); it acts via the enkephalin receptor pathway.

Pentapeptide-18 binds to the delta-opioid receptor (Δ-Opioid Receptor) on the presynaptic membrane of nerve cells.

Receptor activation triggers conformational changes, leading to the release of the G protein complex (comprising α, β, and γ subunits).

The G protein signaling cascade leads to the closure of calcium ion channels and a decrease in intracellular calcium concentration.

Calcium ions are essential for vesicle fusion and neurotransmitter release; a decrease in calcium concentration prevents vesicle fusion.

Acetylcholine release is inhibited, and neurons remain in a non-excitatory state.

Decreased muscle contraction, reduction in expression lines and dynamic wrinkles

Synergistic effects with Argireline – a dual anti-wrinkle pathway

Pentapeptide-18 and Argireline target different aspects of neuromuscular signal transduction.

When used in combination, both peptides simultaneously block neuromuscular signal transmission at both upstream and downstream levels. Clinical data demonstrate that wrinkle depth can be reduced by up to 47%, showing significantly enhanced efficacy compared to the use of either peptide alone.

Clinical efficacy data

Apply a cream containing 0.005% pentapeptide-18 twice daily; after 28 days, the depth and width of periorbital wrinkles show significant improvement.

When using products containing a 5% Leuphasyl solution, the reduction in wrinkle depth was approximately 11.64% when used alone after 28 days; this effect increased to nearly 50% when combined with Argireline.

Independent study (n=30 women aged 40–55 years, 12 weeks): Average reduction in wrinkle volume by 27%, improvement in skin elasticity by 21%, and histological analysis revealed increased dermal density with improved collagen organization.

Consumer perception study: Over 85% of participants reported significant improvement in fine lines, particularly around the eyes and forehead.

Muscle contractility can decrease by 30%-40%.

Enhance skin hydration, firmness, and radiance

In addition to its anti-wrinkle efficacy, pentapeptide-18 also enhances the skin's moisture retention capacity, firmness, and radiance, with no significant adverse effects reported in clinical applications.

Reference proportions for addition to cosmetics

Lyophilized powder (raw material powder)

Note: The clinically validated effective pure peptide concentration is 0.005% (50 ppm), with a recommended formulation addition range of 100–500 ppm.

Applicable Product Types

Anti-aging/anti-wrinkle essence, face cream, lotion

Eye cream (for crow's feet and fine lines under the eyes)

Forehead anti-wrinkle product (targeting forehead wrinkles)

Nursing products for the forehead crease

Mask (patch-type/moisturizing type)

Neck care products

Post-medical aesthetic restoration products (non-invasive botulinum toxin alternative therapy)

Formulation Precautions

Administration timing: Add during the final stage of cosmetic production (low-temperature phase), with temperature not exceeding 40°C, to avoid peptide chain degradation caused by high temperatures.

pH range: The recommended formulation pH should be controlled between 5.0 and 7.0.

Compatibility: exhibits excellent compatibility, particularly when combined with other neurotransmitter inhibitory peptides and signal peptides.

Gold Combination Formula:

Pentapeptide-18 + Argireline (acetylated hexapeptide-8) – dual neurotransmitter inhibition with synergistic effects, achieving up to 47% reduction in wrinkles

Pentapeptide-18 + Matrixyl 3000 (Palmitoyl tripeptide-1 + Palmitoyl tetrapeptide-7) – inhibits dynamic wrinkles and promotes collagen synthesis, providing comprehensive anti-aging effects.

Pentapeptide-18 + Hyaluronic Acid – Muscle relaxation and wrinkle reduction + Deep hydration

Pentapeptide-18 + SNAP-8 (Acetyloctapeptide-3) – a multi-target SNARE inhibitor

Safety: Mild and non-irritating; no significant adverse reactions when applied topically; suitable for all skin types including sensitive skin.

Advantages of D-alanine modification: The second amino acid adopts the D-conformation of alanine, significantly enhancing resistance to enzymatic degradation and improving stability and longevity in the skin.