12 minute read
Exploring Peptides in Skincare
Dr Dev Patel provides an introduction to the role of peptides in skincare
‘Peptides’ is a commonly used term by aesthetic industry professionals, but is also well recognised by the ‘skingeek’ consumer, ever-seeking the latest ingredient to reverse the signs of ageing. Here, we take a journey into peptides and their application in cosmetic dermatology.
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What are peptides? Peptides are essentially small pieces of protein. In fact, the term comes from the Greek term pepton peptos, which means digested.1 They are chains (polymers) of amino acids – the building blocks of proteins – and, if you link two amino acids together, you have a ‘dipeptide’, three amino acids resulting in a ‘tripeptide’, then a ‘tetrapeptide’ and so on. Peptides typically consist of less than 50 amino acids. ‘Oligopeptides’ have less than 20 amino acids. The term ‘protein’ is used for larger chains, and these may contain ‘polypeptides’, a long chain of peptides joined together.2 Naturally occurring human peptides are key in cell-to-cell communication, for example, protein regulation, cell migration and proliferation, inflammation, melanogenesis and angiogenesis, resulting in a wide variety of physiological processes including immunity, stress, growth, homeostasis and reproduction.1 Peptides may be either natural protein fragments – due to enzymatic or acid hydrolysis – and thus of undefined fragment size, or synthetic peptides. The former is not consistent in the end product, whereas synthetic peptides are. Around 1,400 synthetic peptides are listed in the International Nomenclature of Cosmetic Ingredients (INCI) database directory, although only a few have widespread use and recognition.3
100 years of peptides The first peptides were described by chemist Emil Fischer and scientist Franz Hofmeister in the early 1800s and the first peptide synthesis was published in 1901 by chemists Emil Fischer and Ernest Fourneau.4 Fischer went on to describe dipeptides, tripeptides and polypeptides. It was exactly a century ago, in 1921, that glutathione – a potent, naturally occurring intracellular antioxidant – was named and suggested as a peptide by biochemist Frederick Gowland-Hopkins. It was first discovered by physician J. de Rey-Paihade in 1888 from extracts of yeast and various animal tissue; then named philothion. By 1929, Hopkins had proposed the correct tripeptide structure of cysteine-glutamate-glycine which was later confirmed by a number of scientists.5 Glutathione is commonly found in skincare products today, especially those aiming at skin-brightening. Interestingly, it was in the same year (1921) that physicians Frederick G. Banting and Charles Best reported their discovery of insulin to the American Physiological Society, a discovery that would go on to improve the quality of life for millions of people with diabetes and continues to do so to this current day.6 In 1955, British biochemist Frederick Sanger successfully sequenced bovine insulin and discover its exact amino acid composition, which later won him the Nobel Prize for Chemistry.7 Other important peptide discoveries include oxytocin, angiotensin and growth hormone.8 Within the skincare realm, various natural peptides have been identified and synthetic ones formulated, with everincreasing knowledge of their function. Copper glycine-histidine-lysine (Cu-GHK) was developed in 1973 by biochemist Loren Packard, and by the late 1980s the first copper peptide was formulated into a skincare product. However, it took until 2000 for the most significant turning point to happen, when palmitoyl pentapeptide-4 was introduced under the brand name Matrixyl. Over the last 20 years, numerous short and stable synthetic peptides have been developed, demonstrating a role in extracellular matrix synthesis, pigmentation, innate immunity and inflammation.1
Benefits of peptides in skincare Peptides are not limited to cosmetic dermatology as the aforementioned discoveries indicate. In fact, their application in medical dermatology predates their cosmetic use. Pimecrolimus and tacrolimus, two widely used immune-modulators, indicated for atopic dermatitis, are both ‘peptides’.
Peptides can fulfil a variety of functions in cosmetic dermatology. Most activities are centred on:8
• Tissue repair (wrinkle reduction, firming, stretch marks, puffy eyes) • Botulinum toxin-A-like activity to prevent and smooth wrinkles • Skin whitening and tanning • Slowing hair loss • Anti-inflammatory activity (soothing) • Anti-microbial action
Mode of action As proteins, peptides play a whole host of vital functions in the body. A key limiting factor when used topically is their permeability. In part, this is influenced by physiochemical properties of the peptide, for example, acid-dissociation constant (pKa), molecular size, stability, binding affinity, and solubility.8 Thus, putting a bunch of peptides into a jar and hoping they will induce biological antiageing is not realistic. The individual peptides and the properties of the final collective formulation must fulfil a long list of chemical criteria to ensure the product will deliver what it claims to. Peptides by nature are not good candidates for diffusing through the stratum corneum (uppermost layer of the epidermis) which is lipophilic, consisting of only 13% water.8 Small molecules lacking in hydrogenbinding groups exhibit the highest degree of diffusion. Peptides often contain many amide bonds (as hydrogen bond donor and acceptor groups) and may be larger in size. Furthermore, at physiological pH they are often charged, making them hydrophilic – not ideal with a lipophilic stratum corneum to cross.8 However, numerous studies have demonstrated adequate diffusion to affect a biological action. Pimecrolimus has relatively poor diffusion but nevertheless manages to be an effective treatment for atopic dermatitis and is a topical drug I often prescribe in my skin clinic.8 Methods applied to improve depth of delivery of peptides include:8
• Penetration enhancers (glycols, surfactants) • Delivery vehicles (liposomes, nanopeptides) • Chemical modifications such as palmitoylation – this is adding a fatty acid chain which can increase penetration by up to 1,000 times through the stratum corneum
Signal peptides These act as hormones or messengers. In vivo, inflammation triggers proteases and other enzymes to break down collagen, fibronectin, hyaluronic acid and other substances. These resulting smaller strands/fragments (matrikines) then act as hormones or messengers to stimulate fibroblasts and other cells as part of a response of repair and regeneration.1 Matrikines are capable of regulating cell activities by interacting with their specific receptors. They activate certain genes involved in the process of extracellular matrix renewal and cell proliferation. These mechanisms become weaker and weaker with age. Signal peptides stimulate production of extracellular matrix (ECM) proteins including collagen, fibronectin, elastin, and proteoglycans, by communicating with specific cells such as fibroblasts. These proteins are key to the structural integrity and hydration of our skin cells, and by upregulating their production, signal peptides can deliver firmer, tighter and brighter skin. One of the original signal peptides used in skincare is discussed below.8
KTTKS and Matrixyl In 1993, Katayama et al. showed that lysine-threonine-threonine-lysine-serine (KTTKS) is the smallest natural fragment (of collagen 1) that has collagen-stimulating potential.9 Seven years later, Matrixyl was developed as a synthetic replica of this pentapeptide structure. It is a small, highly specific biologically active peptide, shown to stimulate production of ECM proteins (including collagen Types I, III and IV), support of the ECM matrix and wound healing. A number of placebo-controlled, double-blind randomised studies (some biopsy-based) have demonstrated the ability of pal-KTTKS to reduce fold depth and thickness and skin rigidity as well improving other skin quality parameters.10-13 Furthermore, no risk of irritation, sensitisation, mutagenicity or acute toxicity was identified.
Carrier peptides Carrier peptides facilitate delivery of key trace elements (e.g. copper and manganese) essential for wound healing and other enzymatic processes. Certain carrier peptides have also been developed which accelerate and facilitate delivery of bioactive molecules into the skin.14 In a double-blind randomised controlled trial consisting of 67 subjects using glycyl-l-histidyl-l-lysine (Cu-GHK) or placebo twice daily for 12 weeks,
Type of peptide Mechanism of antiageing Examples
Signal peptides
Carrier peptides They activate certain genes involved in the process of extracellular matrix renewal and cell proliferation, thereby increasing ECM proteins and glycosaminoglycans (GAGs) e.g. collagen, elastin, fibronectin, laminin • Palmitoyl Tripeptide-1 • Palmitoyl Tetrapeptide-7
Improve dermal delivery of trace elements essential for enzymatic processes (wound healing) • Copper peptide-GHK • Manganese tripeptide-1
Neurotransmitter-inhibiting peptides To reduce contraction of facial muscles of expression and thus wrinkles • Acetyl octapeptide-3 • Pentapeptide-18
Enzyme inhibitor peptides Inhibit enzymes related to ageing process • Black rice oligopeptides • Soybean peptide
Cu-GHK showed impressive results over the placebo group. Cu-GHK improved skin laxity, clarity and appearance, lines and wrinkles, and mottled hyperpigmentation, as well as skin density and thickness.15 Several other studies confirming the beneficial actions of Cu-GHK have been performed. These actions include increasing keratinocyte proliferation, improving appearance, firmness, elasticity, skin thickness, wrinkles, spotty hyperpigmentation and light damage, skin collagen, strengthening proteins of skin protection barrier, and improvement of skin appearance.1,16
Neuropeptides Neurotransmitter inhibitor peptides (neuropeptides) are peptides that act in the brain (reducing pain, inducing happiness, inducing sleep, suppressing appetite) but many can also be found in the skin, for example, neurotensin, substance P, encephalin, beta-Endorphin, alpha-MSH.10 So how can these be applied in aesthetic medicine? The muscles of facial expression, especially in the upper face, are a key contributor to the formation of lines and wrinkles in this area, such as periorbital lines. Nerves signal muscles to contract via the neurotransmitter aetylcholine (ACh). Botulinum toxin-A (BoNT-A) is a well-established cosmetic treatment for the prevention and treatment of lines and wrinkles of the upper face. BoNT-A cleaves SNAP-25 – a critical protein for ACh release – thus ultimately resulting in muscle relaxation. Topical synthetic peptides which can inhibit neurotransmitter release have been identified. These cosmeceutical peptides penetrate skin and relax muscles, causing the reduction and softening of wrinkles and fine lines.1
Acetyl-hexapeptide-3 Acetyl-hexapeptide-3 (also known as Argireline) is a synthetic peptide which imitates the N-terminal end of the SNAP-25 protein and thus inhibits SNARE complex formation and catecholamine release. Inhibition of noradrenaline and adrenaline release has also been demonstrated. In one of many studies, Argireline was shown to reduce wrinkles by 30% vs. 10% in placebo in just four weeks.17 Later, a two amino acid addition produced acetyl-octapeptide-3 (SNAP-8) which has a superior action on wrinkles compared to its predecessor.17
Enzyme inhibitor peptides These directly or indirectly inhibit an enzyme. Rice peptides, for example, inhibit matrix metalloproteinase (MMP) activity. Although important in tissue remodelling, MMPs degrade the ECM and their upregulation accelerates ageing and cancer. Soybean peptides extracted from soybean seeds, inhibit the formation of proteinases.18 A small pseudo-randomised study of just 10 women (in vivo/in vitro) with soybean peptide, showed a significant increase in glycosaminoglycan and collagen synthesis.19 Although this and other small studies1 have shown potential antiageing benefits, larger studies are required as well as more in vivo trials to better demonstrate the relevance and potential of these peptides in skincare formulations. Although, so far, their role looks to be very promising.
What are growth factors? Growth factors are naturally occurring proteins (polypeptides) or hormones, capable of stimulating cell proliferation or differentiation and potentiating wound healing. Growth factors are important for regulating a variety of cellular processes. In skincare, both naturally derived and synthetic growth factors have been used with powerful effects. The best known is epidermal growth factor (EGF) or Oligopeptide-1, which promotes the proliferation of mesenchymal, glial and epithelial cells. I use topical growth factors extensively in my clinical practice.20 The scope and potential of growth factors in dermatology is significant and goes beyond the scope of this article.
Effective antiageing formulas The use of peptides in cosmetic dermatology has been well established over the last two decades. The most commonly applied peptides are signalling/messenger peptides which primarily strengthen the extracellular matrix, and neurotransmitterinhibitor peptides which prevent and treat expression lines through muscle relaxation. Numerous placebo-controlled, double-blind, randomised controlled trials have supported the claims of efficacy of these peptides for antiageing purposes. As practitioners, the most important issue we must remain aware of is that peptides are inherently poor diffusers of the stratum corneum. Only formulations with effective molecular delivery technology, will allow these peptides to perform their desired biological action, which if achieved, offers your patients a very safe and clinically effective option for attaining healthier skin.
Dr Dev Patel is a KOL for InMode UK and a Merz Innovation Partner and educator for Merz UK, and also trains on behalf of his training facility, Perfect Skin Academy. He has won more than seven awards, personally and on behalf of his clinic, Perfect Skin Solutions and recently launched his own skincare brand, CellDerma. He regularly speaks at major global conferences and has taught medical professionals in the US, China, and Norway. Qual: BSc(Hons), MB BS, Dip IMC RCS(Ed), DFFP, Dip Prac Dermatology, MRCGP, DOccMed
REFERENCES
1. Schagen S.K. “Topical peptide treatments with effective antiaging results.” Cosmetics 2017 2. The University of Queensland, Australia. Explainer: Peptides
Vs proteins – what’s the difference. Nov 2017. <https://imb. uq.edu.au/article/2017/11/explainer-peptides-vs-proteins-whatsdifference> 3. Personal Care Records Council, International Nomenclature
Cosmetic Ingredient, <https://www.personalcarecouncil.org/ resources/inci> 4. Fischer E, Fourneau E. “Ueber einige derivate des Glykolls” Eur.
J. Inorg. Chem, (34) 2868-2867, 1901. 5. Amer et al. Profiles of Drug Substances, Excipients and Related
Methodology, 2015. 6. Banting F.G, Best C.H et al., “The internal secretion of the pancreas,” December, 1921 7. Vecchio et al. The discovery of insulin: An important milestone in the history of medicine, Front Endocrinol (Lausanne), (9): 613, 2018 8. Gorouhi F, Maibach H.I. “Role of topical peptides in preventing or treating aged skin”, International Journal of Cosmetic
Science, 2009, 31, 327–345, 2009. 9. Katayama K, et al., “A pentapeptide from Type I procollagen promotes extracellular matrix production”, The Journal of
Biological Chemistry, Vol 268, 14(15), Issue of May 15, 9941-9944, 1993. 10. Lintner, K. “Cosmetic or Dermo Pharmaceutical Use of Peptides for Healing, Hydrating and Improving Skin Appearances during
Natural or Induced Ageing (Heloderma, Pollution)”, US Pattent 6(620) 419, September 2003. 11. Kaczvinsky, J.R.; Griffiths, et al., “Efficacy of anti-aging products for periorbital wrinkles as measured by 3-D imaging”, J. Cosmet.
Dermatol. 2009, (8) 228–233, 2009. 12. Robinson, L.R. Fitzgerald, et al., “Topical palmitoyl pentapeptide provides improvement in photoaged human facial skin, Int. J.
Cosmet. Sci, (27) 155–160, 2005. 13. Mondon, P., Hillion, M, et al., “Evaluation of dermal extracellular matrix and epidermal-dermal junction modifications using matrix-assisted laser desorption/ionization mass spectrometric imaging, in vivo reflectance confocal microscopy, echography, and histology: Effect of age and peptides”, J. Cosmet. Dermatol, (14) 152-160,2015. 14. Snyder, E.L. and Dowdy, S.F., “Recent advances in the use of protein transduction domains for the delivery of peptides, proteins and nucleic acids in vivo”, Expert Opin. Drug Deliv, (2) 43–51, 2005. 15. Finkey, M.B., Appa, Y., et al., “Copper peptide and skin. In:
Cosmeceuticals and Active Cosmetics”, Marcel Dekker, New
York, 549-564, 2005. 16. Pickart, L., Vasquez-Soltero, et al., “GHK Peptide as a Natural
Modulator of Multiple Cellular Pathways in Skin Regeneration”,
BioMed Res. Int. 2015. 17. Blanes-Mira, C., Clemente, J., et al., “A synthetic hexapeptide (Argireline) with antiwrinkle activity”, Int. J. Cosmet. Sci, (24), 303–310, 2002. 18. Rull, M., Davi. C, et al., “Peptide Approach to Enhance Antiwrinkle Efficacy Between Injections”, Cosmetics and Toiletries, 2014 19. Andre-Frei, V. Perrier, et al., “A comparison of biological activities of a new soya biopeptide studied in an in vitro skin equivalent model and human volunteers” Int. J. Cosmet. Sci, (21), 299–311, 1999. 20. C. Aldag, D. Teixeira, et al., “Skin rejuvenation using cosmetic products containing growth factors, cytokines and matrikines: a review of the literature, Clin Cosmet Investig Dermatol, (9), 411-419, 2016.
