Cosmeceuticals are a unique but growing category of skincare products that combine the effectiveness of pharmaceuticals with the aesthetic appeal of cosmetics.
Created using actives designed to improve skin health and appearance, they offer great promise for a more targeted approach to their skincare routine. Here we will be exploring peptides – one of the most popular and effective cosmeceutical ingredients now produced in synthetic form.
Growing knowledge of both natural peptide mechanisms and development techniques has fed into a wide range of different synthetic peptides with an array of functions and benefits for the skin. Low molecular weight peptides, for example, can be designed with optimized bioactivity and penetration capabilities for use in skincare (also with the support of biotech), with benefits such as improved skin health and resilience or prevention of skin aging. Antimicrobial peptides (AMPs) have also been artificially created in a laboratory to mimic the structure and function of natural antimicrobial peptides, offering anti-pathogenic applications as well as the potential to help combat antimicrobial resistance.
Here we will explore the science and development of synthetic peptides, and consider the potential implications for the skin microbiome.
What are peptides and synthetic peptides?
Peptides are short chains of amino acids (the building blocks of proteins), and are found naturally in the skin. Naturally occurring peptides are known to act in cellular communication, such as protein regulation, as well as cell proliferation, cell migration, inflammation, angiogenesis and melanogenesis. Through this, peptides contribute to a broad variety of physiological processes, including defence, immunity, stress, growth and homeostasis [1].
There are a range of different peptide types. One, for example, being AMPs. AMPs are highly diverse and dynamic molecules produced by various organisms, including microorganisms, and have multifunctional roles. On the skin alone, AMPs can regulate skin microbial composition and provide protection from microbial infection, as well as supporting skin barrier homoeostasis, modulation of inflammation responses and wound healing. AMP expression changes in the skin have even been linked the pathogenesis of skin conditions, including acne vulgaris, atopic dermatitis and psoriasis [2,3,4]. AMPs are also expressed by certain intestinal epithelial cells and immune cells in the gastrointestinal tract. Here they play critical roles in maintaining tolerance to gut microbiota and protecting against enteric infections, as well as inflammatory conditions such as inflammatory bowel disease [5].
Synthetic peptides are created in a laboratory and are designed to mimic the effects of natural peptides in the skin. Initially, the main cosmeceutical application of synthetic peptides was their use as carriers for larger molecules. As synthetic peptides could be developed and modified in various ways to enhance elements such as skin penetration, receptor binding, stability and solubility, the resulting products could overcome challenging skin properties that hinder major ingredients in drugs or cosmetics – such as multilayering, lipophilicity and the presence of numerous active enzymes [1,6,7].
More recently, a deeper knowledge of the biological functions of many different peptides has widened the potential of synthetic peptides and enabled their use as cellular regulators. Synthetic peptides are now widely used in the cosmeceutical field, with some well-known sequences structurally modified over time to achieve new physicochemical properties and increased bioactivity – as well as further improved penetration and stability, especially in the case of dry and aged skin [7]. For example, synthetic peptides can now be used to help stimulate collagen production, improve skin texture and tone, and reduce the appearance of fine lines and wrinkles [1,6]. In the case of AMPs, these peptides are usually made up of longer and more complex chains. However, with the help of biotech or by isolating the AMPs from specific materials (such as egg white lysozyme), it is now possible to replicate the structure.
What are the different types of synthetic peptides?
Increasing knowledge around natural peptides and their mechanisms has fed into a broad spectrum of synthetic peptides within the cosmeceutical field, which act via inhibition or agonism of specific targets. Key categories of topical cosmeceutical peptides that are now available or are in development include signal peptides, carrier peptides, neurotransmitter inhibitor peptides and enzyme inhibitor peptides, as well as synthetic AMPs [1,8].
Signalling peptides
Several peptides are able to trigger a signalling cascade. They are released from the extracellular matrix and increase the proliferation of collagen, elastin, proteoglycan, glycosaminoglycan and fibronectin – types of protein that play important roles in skin structure and function. As a result, pigmentation of photodamaged skin, fine lines and wrinkles are reduced through the regeneration of the skin matrix cells. Skin elasticity increases, and skin appears smoother and firmer. Synthetic peptides modelled on repair signalling sequences have therefore been developed to rejuvenate skin [1,6].
Carrier peptides
Carrier peptides are involved in the transport of trace elements, such as copper or manganese, into skin cells to help support enzyme function [1]. Copper, for example, is a crucial metal ion within the human body and can be stabilized or delivered into cells by peptides. It is incorporated in various processes, including wound healing and angiogenesis. In the case of cosmeceuticals, copper is targeted to help increase the formation of collagen or elastin to support such processes, and can also help prevent premature skin aging [6].
Neurotransmitter inhibitor peptides
Neurotransmitter inhibitor peptides penetrate the skin and relax muscles, leading to anti-aging benefits such as reduced and softened wrinkles and fine lines. Synthetic peptides can mimic these effects by acting via the muscle contraction mechanism. Muscles are contracted when neurons release neurotransmitters, which is mediated by certain receptor proteins. These proteins form the SNARE complex, which acts in a pathway of various processes to induce muscle contraction. Synthetic peptides that mimic the amino acid sequence of proteins within this complex have been shown to specifically inhibit neurosecretion and thus reduce muscle contraction [1].
Enzyme inhibitor peptides
Enzyme inhibitor peptides directly or indirectly inhibit enzymes (although it should be noted that synthetic peptides can also act as agonist).
A recent in vivo clinical study reinforced these results and demonstrated that SYN-UP (a synthetic peptide derivative that boost skin’s resilience against stress attacks, designed for use as a moisturizing and rebalancing agent) can also help fight against dry skin conditions and skin redness due to its interaction with common skin bacteria – for example, by boosting levels of Staphylococcus epidermidis and reducing Staphylococcus aureus levels, breaking S. aureus-related inflammatory cycles (find out more about SYN-UP here).
Antimicrobial peptides
Given the low bioavailability of relevant AMPs in nature, biotechnological interventions with genetic engineering and synthetic biology strategies for enhanced AMP synthesis have been a key focus in industry [9]. With this, as synthetic peptide development approaches have improved, the potential of synthetic AMPs to counteract pathogens and emerging infections has grown – they can now be designed with multifaceted mechanisms of action and act as antiviral, antibacterial and antifungal agents.
Key categories of AMPs currently in development include receptor-binding peptides, membrane-active peptides, membrane-lytic peptides and inhibitory peptides (such as cell wall-inhibiting peptides) [8]. AMPs generally affect highly preserved structures and can be used against specific targets such as peptidoglycans in Gram-negative and Gram-positive bacteria, and glucan in the fungal cell wall. Other peptides are particularly active on biofilm destabilizing the microbial communities. Synthetic peptides have also been marked as a potential solution to help combat antibiotic-resistant microbes such as drug-resistant Staphylococcus aureus [10,11]. They can also act intracellularly – for instance, on protein biosynthesis or DNA replication [12].
As well as mimicking pharmacological properties, structural and amino acid sequence improvements can also be used to address challenges associated with natural AMPs, such as instability when used as a drug, host toxicity, rapid degradation by proteases and loss of activity in presence of serum and high salt concentrations [8,12]. Short-sequence AMPs (<20 amino acids) can be used to combine optimal antimicrobial activity with inexpensive chemical synthesis and modifications required to ensure stability, low toxicity and microbial specificity, and are compatible with large-scale production [13].
Future work
Extensive research has been carried out in terms of the discovery, production and optimization of peptides, in order to overcome drawbacks such as membrane impermeability and poor stability in vivo. Synthetic peptides are now widely used in the cosmeceutical field, with a growing bank of data to support their stability and safety and a number of studies demonstrating the wide range of possible topical cosmetic applications of the biologically active peptides for the skin.
However, the field will benefit from the acquisition of more in-depth knowledge of the different molecules, as well as the physiological principles underlying their use. This should include identifying the mode of action and effects of each individual peptide, and clearly defining it for cosmetic or pharmaceutical application. The effects of the different types of synthetic peptides on the skin microbiome are also yet to be investigated in most cases. The microbiome is likely to benefit from a maintained or improved healthy skin environment, but it may be that future research will reveal new impacts of peptides on skin microbes (besides only having antimicrobial properties).
In terms of production, the single and combined use of biological and chemical recombination synthetic approaches has enabled the efficient and reliable production of synthetic peptides at large scale. These peptides can be further modified in a site-specific manner through chemical synthesis or genetic code expansion to enhance their stability and physiological activity [14]. However, the integration of traditional peptide discovery methods (such as rational design and phage display) with novel technologies and advanced methods (such as AI processes) also provides a promising approach for the development and production of effective and selective lead peptides in a short period of time – and could lead to a new wave of next-generation peptides.
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References
1. Schagen, S. K. Topical peptide treatments with effective anti-aging results. Cosmetics 4, 16 (2017).
2. Herman, A. & Herman, A. P. Antimicrobial peptides activity in the skin. Skin Res Technol . 2019 Mar;25(2):111-117.
3. Moretta, A. et al. Antimicrobial Peptides: A New Hope in Biomedical and Pharmaceutical Fields. Front. Cell. Infect. Microbiol. https://doi.org/10.3389/fcimb.2021.668632 (2021).
4. Rademacher, F. et al. Antimicrobial peptides and proteins: Interaction with the skin microbiota. Exp. Dermatol. 10.1111/exd.14433 (2021).
5. Gubatan, J. et al. Antimicrobial peptides and the gut microbiome in inflammatory bowel disease. World J. Gasteroenterol. 27, 7402-7422 (2021).
6. Errante, F. et al. Cosmeceutical peptides in the framework of sustainable wellness economy. Front. Chem. 8, 572923 (2020).
7. Ledwon, P. et al. Peptides as active ingredients: a challenge for cosmeceutical industry. Chem. Biodivers. 18, e2000833 (2021).
8. Chen, C. H. & Lu, T. Development and Challenges of Antimicrobial Peptides for Therapeutic Applications. Antibiotics 10.3390/antibiotics9010024 (2020).
9. Sinha, R. & Dhukla, P. Antimicrobial Peptides: Recent Insights on Biotechnological Interventions and Future Perspectives. Protein & Peptide Letters 26, 79-87 (2019).
10. Souza, P. F. N. et al. Synthetic antimicrobial peptides: From choice of the best sequences to action mechanisms. Biochimie 175, 132-145 (2020).
11. Mohamed, M. F. et al. Evaluation of short synthetic antimicrobial peptides for treatment of drug-resistant and intracellular Staphylococcus aureus. Sci. Rep. 6, 29707 (2016).
12. Vanzolini, T. et al. Multitalented synthetic antimicrobial peptides and their antibacterial, antifungal and antiviral mechanisms. Int. J. Mol. Sci. 23, 545 (2022).
13. Rahnamaeian, M. & Vileinskas, A. Short antimicrobial peptides as cosmetic ingredients to deter dermatological pathogens. Appl. Microbiol. Biotechnol. 99, 8847–8855 (2015).
14. Wang, L. et al. Therapeutic peptides: current applications and future directions. Signal Transduction and Targeted Therapy (2022) 7:48
