Palmitoyl Tripeptide-1 (Pal-GHK)

Synthetic Peptides in Cosmetic Products

Synthetic peptides are peptide ligands that modulate cellular function by stimulating or inhibiting cell receptors. Peptides found in cosmetic products penetrate through the stratum corneum and have a molecular weight of less than 500 Da. The penetrability of peptides can be increased via chemical modifications. Synthetic peptides present in cosmetic products are broadly classified into signal peptides, carrier peptides, neurotransmitter inhibitory peptides, and enzyme inhibitory peptides. Palmitoyl tripeptide-1, previously known as Palmitoyl oligopeptide, is classified as a signal peptide. (Resende et al., 2021)

  • Common Dermatologic Conditions
  • Psoriasis

Psoriasis is referred to as chronic inflammation of the skin marked by epidermal proliferation and infiltration of inflammatory immune cells through the layers of the skin. Underlying pathogenesis involves inflammatory mediators – tumor necrosis factor (TNF), IL-23, and IL-17 – that are involved during the onset of inflammatory cutaneous lesions. The mediators also promote the synthesis and release of antimicrobial peptides, cytokines, and chemokines from the keratinocytes. (Sawada et al., 2021) 

  • Dermatitis 

Contact dermatitis is caused by exposure of skin to toxic chemicals, reactive chemicals, and metal ions. Contact irritants elicit T-cell responses while contact allergens give rise to adaptive and innate immune responses.  The keratinocytes release proinflammatory cytokines in response to the chemical agents. These irritants disrupt the normal skin barrier, induce cellular alterations of the dermis, and promote the secretion of cytokines. Repeated exposure of skin to haptens may give rise to the allergic form of contact dermatitis. (Litchman et al., 2022)

  • Eczema

Eczema, also referred to as atopic dermatitis, is associated with mutations in the gene encoding for filaggrin. Filaggrin protein contributes to the optimal function of the skin barrier in the stratum corneum and moisturization of the skin. Filaggrin gene mutations manifest as a disrupted skin barrier and production of proinflammatory cytokines. (Sawada et al., 2021)

  • Dermal Aging

Dermal aging is characterized by the impaired function of fibroblasts with subsequent reduction in the collagen levels of the dermal extracellular matrix. Dermal aging is also associated with a reduction in the function of regulatory proteins that further disrupt the balance between apoptosis and maturation. Impairment of repair mechanisms leads to accumulation of cellular changes and subsequent decline in cellular functions. Dermal aging also affects glycosaminoglycans, proteoglycans, and elastic fibers. These alterations manifest as wrinkles and reduced elasticity of the skin. Dermal aging is also associated with increased levels of matrix metalloproteinase, which is responsible for the degradation of extracellular matrix proteins. (Flint & Tadi, 2020; Shin et al., 2019)

  • Palmitoyl Tripeptide-1 
  • Composition

Palmitoyl tripeptide-1 is characterized by the sequence N-(1-oxohexadecyl) glycyl-L-histidyl-L-lysine. This synthetic peptide is a collagen fragment that acts as a signal peptide. (Resende et al., 2021) When palmitoyl tripeptide-1 is coupled with copper ion, it becomes a carrier peptide. Palmitoyl tripeptide-1 is used in Matrixyl 3000 in combination with Pal-GQPR and also used in Biopeptide CL. Both the products are manufactured as an anti-aging serum by Sederma. (Errante et al., 2020) Palmitoyl tripeptide-1 is synthesized by a reaction between tripeptide-1 and palmitic acid. Tripeptide-1 is a synthetic peptide that comprises glycine, lysine, and histidine. (Johnson & Heldreth, 2012) Palmitoyl tripeptide-1 has an amphiphilic structure, hence, it is difficult to solubilize the peptide in cosmetic products. (Lintner & Peschard, 2000)

  • Synthesis of Palmitoyl Tripeptide-1

Palmitoyl tripeptide-1 can be synthesized using three distinct methodologies. The first methodology is characterized by EDC-mediated coupling of dipeptide 36 and Pal-Gly-ONb, giving rise to Pal-Gly-His-Lys-OBzl. Removal of Bzl and Cbz from this substance results in the formation of palmitoyl tripeptide-1. (Resende et al., 2021) The second methodology refers to a solid phase approach, using which Smoc –L-Hys, Smoc-Gly, and H-Lys-HMPB-ChemMatrix are coupled together. This is followed by deprotection of the Smoc group, palmitoylation, peptide cleavage, and lyophilization to yield palmitoyl tripeptide-1. (Knauer et al., 2020) The third methodology is characterized by the formation of Boc-Lys-Obzl, followed by the removal of the Boc group, coupling with Boc-His-OH and Boc-Gly-OH, palmitoylation, and deprotection of carboxylic entity to yield palmitoyl tripeptide-1. (Resende et al., 2021) 

  • Safety Profile and Toxicity 

This synthetic peptide is relatively unstable and undergoes rapid degradation by the enzyme, aminopeptidase, to form L-histidyl-L-lysine that is eliminated from the blood. Palmitoyl tripeptide-1 is a nontoxic moiety and does not induce acute oral toxicity. The peptide does not influence body weight gain and does not lead to skin irritation upon repeated dosage. However, ocular reactions are observed following the installation of palmitoyl tripeptide-1 into the conjunctival sac. This includes mild conjunctival reactions including chemosis and redness. The maximum ocular index of palmitoyl tripeptide-1 is 4.7. Palmitoyl tripeptide-1 is a non-irritant substance, only causing slight application upon topical application. In certain cases, slight discoloration of the skin is also observed. Moreover, palmitoyl tripeptide-1 does not induce allergic contact sensitization. Studies quote palmitoyl tripeptide-1 as a very well tolerated substance. Ames test was used for the evaluation of the genotoxicity of palmitoyl tripeptide-1, hence, the substance is termed nongenotoxic. Studies to date do not report data regarding the carcinogenic effects of palmitoyl tripeptide-1. (Johnson et al., 2018)

  • Cosmetic Benefits of Palmitoyl Tripeptide-1
  • Anti-Aging Activity

Palmitoyl tripeptide-1 stimulates the synthesis of collagen and glycosaminoglycan with subsequent reduction in the roughness amplitude, length, and depth of wrinkles. This demonstrates the anti-wrinkle effect of palmitoyl tripeptide-1. Since wrinkles arise due to relative depletion of collagen in the skin, increased production of collagen as induced by palmitoyl tripeptide-1 has favorable outcomes. The activity of palmitoyl tripeptide-1 is comparable to retinoids, however, the peptide does not cause skin irritation. During the onset of aging, the skin tends to lose its thickness and undergoes a faster rate of thinning, with approximately a 6% reduction in thickness every 10 years. (Errante et al., 2020; Johnson & Heldreth, 2012)

  • Collagen and Fibronectin Synthesis 

Palmitoyl tripeptide-1 tends to promote collagen synthesis by the fibroblasts. Evidence suggests that the copper complex of palmitoyl tripeptide-1 is responsible for this action. The tripeptide – lysine, glycine, and histidine – is a collagen fragment that is released upon hydrolysis of collagen catalyzed by the enzyme collagenase such as during wound healing and inflammatory processes. The release of this collagen fragment acts as a feedback signal for the fibroblasts to synthesize newer tissue matrix molecules including collagen. Studies demonstrate that palmitoyl chain attachment and copper ion conjugation does not influence the collagen-producing activity of palmitoyl tripeptide-1. At the given concentration of 0.5 µML-1, the collagen synthesis signal is observed to be at maximum. Degradation of dermal collagen caused by irradiation with ultraviolet A light followed by treatment of the affected area with palmitoyl tripeptide-1 demonstrate preservation and complete renewal of the dermal collagen. (Lintner & Peschard, 2000)

  • Skin Regeneration

The repair and protective mechanisms of the skin decline as the person grow older. The amino acid sequence of palmitoyl tripeptide-1 is found in the alpha 2 chains of the type I collagen. Following activation of proteolytic enzymes, the peptide is released into the injured area and promotes the synthesis of collagen, glycosaminoglycans, and proteoglycan decorin. The peptide also modulates the catalytic activity of anti-proteases and metalloproteinases, thus, regulating the cutaneous protein breakdown. This prevents the accumulation of damaged proteins as well as prevents excessive proteolysis. Palmitoyl tripeptide-1 also stimulates the release of collagen and fibroblast growth factors from fibroblasts. The skin regeneration is also improved via stimulation of epidermal basal cells and increased expression of integrins and p63. (Huang et al., 2007; Kang et al., 2009; Pickart & Margolina, 2018)

  • Wound Healing

Palmitoyl tripeptide-1 enhances wound healing by improving the contraction of the wound, synthesis of granular tissue, greater catalytic activity of antioxidant enzymes, and promoting the growth of blood vessels. Cutaneous regions treated with palmitoyl tripeptide-1 demonstrate increased levels of ascorbic acid and glutathione with increased activation of mast cells and collagen-producing fibroblasts. However, individuals suffering from bedsores and diabetic skin ulcers demonstrate settling of bacteria on the wound which leads to degradation of this peptide, transforming growth factor, and platelet-derived growth factor. (Arul et al., 2005; Canapp et al., 2003; Cangul et al., 2006; Gomes et al., 2017; Gul et al., 2008)

  • Antioxidant and Anti-inflammatory 

The antioxidant properties of palmitoyl tripeptide-1 protect the skin keratinocytes against ultraviolet radiations of the sun. This also promotes the activity of antioxidant enzymes as well as inactivates the free radicals including glyoxal, 4-hydroxynoneal, malondialdehyde, and acrolein which are lipid peroxidation by-products. Moreover, palmitoyl tripeptide-1 prevents low-density lipoprotein oxidation, suppressing the synthesis of free radicals. The peptide binds to lipid peroxidation products and prevents these from exerting damaging effects. (Beretta et al., 2008; Beretta et al., 2007; Cebrián et al., 2005) Palmitoyl tripeptide-1 reduces the iron that is released by ferritin, which otherwise catalyzes lipid peroxidation. (Miller et al., 1990)


Arul, V., Gopinath, D., Gomathi, K., & Jayakumar, R. (2005). Biotinylated GHK peptide incorporated collagenous matrix: A novel biomaterial for dermal wound healing in rats. J Biomed Mater Res B Appl Biomater, 73(2), 383-391. 

Beretta, G., Arlandini, E., Artali, R., Anton, J. M., & Maffei Facino, R. (2008). Acrolein sequestering ability of the endogenous tripeptide glycyl-histidyl-lysine (GHK): characterization of conjugation products by ESI-MSn and theoretical calculations. J Pharm Biomed Anal, 47(3), 596-602. 

Beretta, G., Artali, R., Regazzoni, L., Panigati, M., & Facino, R. M. (2007). Glycyl-histidyl-lysine (GHK) Is a Quencher of α,β-4-Hydroxy-trans-2-nonenal: A Comparison with Carnosine. Insights into the Mechanism of Reaction by Electrospray Ionization Mass Spectrometry, 1H NMR, and Computational Techniques. Chemical Research in Toxicology, 20(9), 1309-1314. 

Canapp, S. O., Jr., Farese, J. P., Schultz, G. S., Gowda, S., Ishak, A. M., Swaim, S. F., Vangilder, J., Lee-Ambrose, L., & Martin, F. G. (2003). The effect of topical tripeptide-copper complex on healing of ischemic open wounds. Vet Surg, 32(6), 515-523. 

Cangul, I. T., Gul, N. Y., Topal, A., & Yilmaz, R. (2006). Evaluation of the effects of topical tripeptide-copper complex and zinc oxide on open-wound healing in rabbits. Veterinary Dermatology, 17(6), 417-423. 

Cebrián, J., Messeguer, A., Facino, R. M., & García Antón, J. M. (2005). New anti-RNS and -RCS products for cosmetic treatment. Int J Cosmet Sci, 27(5), 271-278. 

Errante, F., Ledwoń, P., Latajka, R., Rovero, P., & Papini, A. M. (2020). Cosmeceutical Peptides in the Framework of Sustainable Wellness Economy. Front Chem, 8, 572923. 

Flint, B., & Tadi, P. (2020). Physiology, aging. 

Gomes, A., Teixeira, C., Ferraz, R., Prudêncio, C., & Gomes, P. (2017). Wound-Healing Peptides for Treatment of Chronic Diabetic Foot Ulcers and Other Infected Skin Injuries. Molecules, 22(10). 

Gul, N. Y., Topal, A., Cangul, I. T., & Yanik, K. (2008). The effects of topical tripeptide copper complex and helium-neon laser on wound healing in rabbits. Veterinary Dermatology, 19(1), 7-14. 

Huang, P. J., Huang, Y. C., Su, M. F., Yang, T. Y., Huang, J. R., & Jiang, C. P. (2007). In vitro observations on the influence of copper peptide aids for the LED photoirradiation of fibroblast collagen synthesis. Photomed Laser Surg, 25(3), 183-190. 

Johnson, W., Bergfeld, W. F., Belsito, D. V., Hill, R. A., Klaassen, C. D., Liebler, D. C., Marks, J. G., Shank, R. C., Slaga, T. J., Snyder, P. W., Gill, L. J., & Heldreth, B. (2018). Safety Assessment of Tripeptide-1, Hexapeptide-12, Their Metal Salts and Fatty Acyl Derivatives, and Palmitoyl Tetrapeptide-7 as Used in Cosmetics. International Journal of Toxicology, 37(3_suppl), 90S-102S. 

Johnson, W., & Heldreth, B. (2012). Safety Assessment of Palmitoyl Oligopeptides as Used in Cosmetics. Cosmetic Ingredient Review, 1-22. 

Kang, Y. A., Choi, H. R., Na, J. I., Huh, C. H., Kim, M. J., Youn, S. W., Kim, K. H., & Park, K. C. (2009). Copper-GHK increases integrin expression and p63 positivity by keratinocytes. Arch Dermatol Res, 301(4), 301-306. 

Knauer, S., Koch, N., Uth, C., Meusinger, R., Avrutina, O., & Kolmar, H. (2020). Sustainable Peptide Synthesis Enabled by a Transient Protecting Group. Angewandte Chemie International Edition, 59(31), 12984-12990. 

Lintner, K., & Peschard, O. (2000). Biologically active peptides: from a laboratory bench curiosity to a functional skin care product. Int J Cosmet Sci, 22(3), 207-218. 

Litchman, G., Nair, P. A., Atwater, A. R., & Bhutta, B. S. (2022). Contact Dermatitis. In StatPearls. StatPearls Publishing

Copyright © 2022, StatPearls Publishing LLC. 

Miller, D. M., DeSilva, D., Pickart, L., & Aust, S. D. (1990). Effects of glycyl-histidyl-lysyl chelated Cu(II) on ferritin dependent lipid peroxidation. Adv Exp Med Biol, 264, 79-84. 

Pickart, L., & Margolina, A. (2018). Regenerative and Protective Actions of the GHK-Cu Peptide in the Light of the New Gene Data. Int J Mol Sci, 19(7). 

Resende, D., Ferreira, M. S., Sousa-Lobo, J. M., Sousa, E., & Almeida, I. F. (2021). Usage of Synthetic Peptides in Cosmetics for Sensitive Skin. Pharmaceuticals (Basel), 14(8). 

Sawada, Y., Saito-Sasaki, N., Mashima, E., & Nakamura, M. (2021). Daily Lifestyle and Inflammatory Skin Diseases. Int J Mol Sci, 22(10). 

Shin, J. W., Kwon, S. H., Choi, J. Y., Na, J. I., Huh, C. H., Choi, H. R., & Park, K. C. (2019). Molecular Mechanisms of Dermal Aging and Antiaging Approaches. Int J Mol Sci, 20(9). 

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