Hexapeptide-2

Summary

Hexapeptide‑2 (Ac‑Lys‑DPhe‑Arg‑Trp‑Dap‑NH₂), also known as acetyl hexapeptide‑2, MC1R antagonist peptide or melanostatine‑5, is a synthetic six‑amino‑acid peptide investigated within the cosmetic and dermatological peptide family. It is intended for topical application in skin‑care research and has not received regulatory approval for therapeutic use. Current studies are limited to in‑vitro and formulation work, and the peptide’s efficacy and safety in humans remain to be demonstrated.

Mechanism of Action

Binds to melanocortin receptors (MC1R) as an antagonist, reducing melanin synthesis by competitively inhibiting alpha-MSH binding, thereby decreasing skin pigmentation and potentially modulating skin tone.

What the Research Shows

Published research on short cyclic and linear hexapeptides provides insight into properties that may be relevant to Hexapeptide‑2, although none of the eight cited papers examine this specific sequence. A 1996 study demonstrated that cyclisation of a model hexapeptide into a pro‑drug reduced its hydrodynamic radius and increased membrane permeability, suggesting that conformational constraints can affect topical delivery. Separate investigations (2002, 2005) identified cyclic hexapeptides composed of alternating α‑aminoxy and α‑amino acids as highly selective chloride‑ion receptors, with binding driven by size complementarity. Conformational analyses (2011) showed that incorporation of α,α‑disubstituted residues can promote 3₁₀‑helical or α‑helical structures in hexapeptides, influencing their stability. A marine‑derived isobutyryl hexapeptide and a Bacillus‑derived cyclic hexapeptide were reported to exhibit enzyme inhibition (proteasome) and modest cytotoxicity, illustrating diverse bioactivities of hexapeptide scaffolds. Collectively, these studies highlight that hexapeptide architecture can modulate membrane transport, ion binding, secondary structure, and enzymatic interactions, but direct evidence for Hexapeptide‑2’s activity is lacking.

Limitations of the Evidence

Evidence specific to Hexapeptide‑2 is currently absent; the available literature addresses other cyclic or modified hexapeptides, leaving its biological activity, efficacy, and safety uncharacterized. No clinical or pre‑clinical studies have reported its effect on melanocortin‑1 receptor signaling, skin pigmentation, or adverse events. Consequently, any claimed cosmetic benefit remains speculative.

How It Is Administered

Hexapeptide‑2 is formulated for topical use and is typically incorporated into creams, gels, or serums intended for skin application in research settings. As a peptide, it is usually delivered in a water‑based or hydrogel base to facilitate contact with the epidermis. No approved pharmaceutical product contains this compound, and its formulation details are limited to experimental preparations.

Routes of Administration

Goals & Uses

• Dark spot treatmentCosmetic / DermatologyLow
• Reduction of hyperpigmentationDermatology / CosmeticLow
• Skin brightening and evening of skin toneCosmeticLow
• Reduction of UV-induced pigmentationPhotoprotection / CosmeticLow

Contraindications

• Application to broken or inflamed skinSkin IntegrityLow
• Known hypersensitivity to peptide componentsAllergyModerate

Adverse Effects

• Local skin irritationDermatologicalUncommon
• Contact dermatitisDermatologicalRare
• Over-depigmentationDermatologicalRare

Drug Interactions

• Other depigmenting agents (e.g., hydroquinone, kojic acid)Low

Population Constraints

• Pregnant or breastfeeding individualsReproductive SafetyRelative
• ChildrenPediatricRelative

Regulatory Status

• European UnionUnapprovedPermitted for cosmetic use under EU Cosmetics Regulation (EC) No 1223/2009 as a cosmetic ingredient.
• United StatesUnapprovedUsed as a cosmetic ingredient only; not FDA-approved as a drug. Regulated under cosmetic category.
• United KingdomUnapprovedConsidered a cosmetic ingredient under UK cosmetics regulations; no drug approval.

Regulated as a cosmetic ingredient in most jurisdictions; not FDA-approved as a drug. Used under cosmetic regulation (e.g., EU Cosmetics Regulation). No clinical drug approval exists.

Evidence & Sources

• The effect of conformation on membrane permeability of an acyloxyalkoxy-linked cyclic prodrug of a model hexapeptide
  Journal ArticleLowGangwar S, et al.1996-01-01T00:00:00.000000Z
• A cyclic hexapeptide comprising alternating alpha-aminoxy and alpha-amino acids is a selective chloride ion receptor
  Journal ArticleLowYang D, et al.2005-01-01T00:00:00.000000Z
• A new xanthostatin analogue from the marine sponge-associated actinomycete Streptomyces sp. SCSIO 40064
  Journal ArticleLowChen S, et al.2022-01-01T00:00:00.000000Z
• Conformational studies on peptides containing α,α-disubstituted α-amino acids: chiral cyclic α,α-disubstituted α-amino acid as an α-helical inducer
  Journal ArticleLowDemizu Y, et al.2011-01-01T00:00:00.000000Z
• Baceridin, a cyclic hexapeptide from an epiphytic bacillus strain, inhibits the proteasome
  Journal ArticleLowNiggemann J, et al.2014-01-01T00:00:00.000000Z
• Cyclic hexapeptide of D,L-alpha-aminoxy acids as a selective receptor for chloride ion
  Journal ArticleLowYang D, et al.2002-01-01T00:00:00.000000Z

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