Techniques aimed at extracting, isolating, characterizing, and synthetizing molecules, as well as techniques for the advanced study of molecular structures, were greatly improved after the second half of the last century. As a result, bioactive peptides or biomimetic peptides were brought to light in the current knowledge. Several peptides with remarkable biological activity were synthetized in the last few years. They can be used in areas ranging from cosmetics, therapeutics, and immunology to even food sciences [1
]. Peptides account for 10% of the sales of pharmaceutical companies, which amounts to US$
25 billion; the commercialization of peptides has been increasing faster than that of small molecules [2
]. Up to 2017, the global cosmeceutical market was estimated to have generated around US$
42.8 billion [3
In this review, emphasis was given to synthetic peptides that are used in cosmeceutical formulations, which can be named either as bioactive, biomimetic, or topical peptides.
Peptides are short chains of amino acids. Some occur naturally in the human body and are known for playing several biological roles, especially as signaling/regulating molecules in a variety of physiological processes, including defense, immunity, stress, growth, homeostasis, and reproduction [4
]. As examples, there are vasodilators, vasoconstrictors, and other substances that act upon cell metabolism:
Substance P can be found in the epidermis, a dipeptide with 11 amino acids that acts as a potent vasodilator contributing to the balance between cell differentiation and cell renewal [6
Peptides somatostin (SOM) and neuropeptide Y found in the skin (NPY—family of endocrine neurotransmitter peptides) play a role on the vascular tonus of the skin by causing vasodilation (by promoting the release of histamine) and vasoconstriction, respectively [6
Adipocytes present in the hypodermis are capable of releasing bioactive peptides, called adipocytokines, such as interleukin-6 (IL-6), leptin, resistin, tumor necrosis factor α (TNF-α), acylation stimulating protein (ASP), and adiponectin [8
Insulin can be considered an example of a polypeptide which acts on cell metabolism, as it facilitates the entry of glucose to the cell interior and interacts with hepatocytes, muscular cells, and adipocytes [9
Biomimetic peptides, on the other hand, are compounds which have an identical amino acid sequence to physiological peptides (oligopeptides with a sequence ranging from 10 to 15 amino acids), but are synthetized biotechnologically. They mimic the action of growth factors and cytokines by interacting with their receptors, leading to clinical effects such as the slowing of aging [10
]. Examples of biomimetic peptides include acetyl decapeptide-3 (Rejuline), oligopeptide-24 (CG-EGP3), oligopeptide-34 (CG-TGP2), and oligopeptide-72 (Boostrin).
Bioactive or topical peptides are also synthetic compounds, but they consist of modified amino acid chains, which improve an already existing physiological function, such as increasing skin permeability, stability, solubility, and better interaction with cell receptors [5
]. Also, several natural physiological processes are signaled and modulated exclusively by interaction with specific amino acid sequences found in certain peptides and protein fragments. Thus, in a technological context, bioactive peptides are becoming increasingly promising as cosmeceuticals with clinical applications in different skin conditions [12
The multiple applications of these synthetic compounds, either biomimetic or bioactive, provide treatment options when used in formulations designed for topical applying, preventing, or attenuating the clinical aspects of skin damaged by dysfunctions: aging, hyperpigmentation, increase of body fat, and wrinkle development [10
]. These peptides can also stimulate the synthesis of collagen and elastin [10
], improve wound healing [15
], increase fibroblast proliferation [10
], and act as growth factors [17
] or even as tensioning and tightening agents [10
Bioactive peptides can be classified according to their mechanism of action in signal, carrier, and neurotransmitter inhibitor peptides [5
The goal of this study was to carry out a literature review on bioactive peptides aiming to describe some of their mechanisms of action and possible applications in cosmetic products. This review might contribute to future research by summarizing relevant information and making it readily available for professionals and researchers interested in the subject.
3. Carrier Peptides
Carrier peptides are responsible for transporting and stabilizing oligoelements such as copper and manganese, carrying them to the skin and allowing their intake by epithelial cells [5
]. Copper is one of the metals which can be transported by such peptides, playing a role on wound healing as well as being a cofactor for enzymes lysyl oxidase, tyrosinase, and superoxide dismutase, which are essential for collagen synthesis, melanogenesis, and superoxide dismutation (antioxidant action) [24
]. Also, these peptides can stimulate key enzyme actions; an example is the tripeptide-copper complex glycyl-l
(copper peptide GHK-Cu or copper tripeptide 1), which not only transports copper, but also increases the tissue levels of metalloproteinases, enzymes responsible for degrading the basic components of the extracellular matrix [15
The effects of GHK-Cu upon metalloproteinase synthesis (MMP-2) by skin fibroblasts in culture were demonstrated by Siméon and collaborators (2000) [24
]. In their study, cultivated fibroblasts treated with GHK-Cu showed increased MMP-2 levels. This was evidenced by increased levels of MMP2 mRNA and increased secretion of tissue metalloproteinase inhibitors (TIMP-1 and TIMP-2). GHK-Cu is also responsible for the remodeling of the extracellular matrix, as it modulates the expression of MMP by acting directly in wound fibroblasts.
A study carried out by Finkley and collaborators (2005) [25
] describes the application of facial creams containing GHK-Cu for 12 weeks on 71 volunteers aged between 50 and 59 years, and the results demonstrated a visible reduction of the effects of aging. In another study by the same authors, they describe the application of the formulation on the eyes of 41 volunteers using similar experimental conditions. At the same time, placebo and controls containing vitamin K were also applied to the subjects. In both studies it was demonstrated that the cream containing GHK-Cu improved the elasticity and tightness of the skin, and also reduced fine lines and deep wrinkles.
Neurocosmetics are cosmeceuticals which contain synthetic neuropeptides that interact with the nervous system through skin mediators [13
]. These compounds can play a role in skin homeostasis by activating or inhibiting such mediators. Skin responses carried out by mediators are regulated by a neuroendocrine system found in the skin capable of initiating adaptation mechanisms through quick pathways (neural pathways) or slow pathways (humoral pathways), acting at both local and systemic levels [33
]. Neurocosmetics can act in the central nervous system, being capable of stimulating the nerve endings of the skin, sending pleasure and well-being “feelings” to the hypothalamus, and causing the release of specific substances on the skin which improve the aspect of skin relief [13
Skin cells release growth factors and proteins that bind insulin, which are synthetized from proopiomelanocortine (POMC), catecholamines, steroidal hormones, vitamin D, eicosanoids from fat acids, and retinoids from diet carotenoids. Skin has developed an autonomous system that responds to local and peripheral stress, which functions by making use of neurotransmitters and hormone peptides in a manner similar to the hypothalamus-hypophysis-adrenal axis [13
POMC peptides are synthetized by melanocytes, keratinocytes, microvascular endothelial cells, annex epithelial cells, mastocytes, Langerhans cells, fibroblasts, and immune cells, such as monocytes and macrophages. POMC, as a precursor protein, leads to the synthesis of several biologically active peptides through a series of enzymatic steps, which are often specific to each tissue, resulting in the formation of melanocyte stimulator hormones (MSHs), corticotrophin (ACTH), and ß-endorphin [13
Fatemi and collaborators (2016) [36
] demonstrated that a peptide derived from POMC, bPOMC, has anti-inflammatory properties and does not disrupt melanogenesis. When skin is exposed to capsaicin, biomimetic peptides are capable of attenuating inflammation by preventing the release of substance P and the actions of IL-8 and IL-1 [34
The same research group, in a double-blind study, employed 56 healthy volunteers with sensitive skin (36 male and 20 female, aged 26 to 40 years) divided into two groups of 28 volunteers each. Both groups received a facial formulation (0.1 g) containing bPOMC, which was used on the right side of the face, and a placebo formulation, which was used on the left side, applied on clean cheeks from the nasolabial to the outer cheek areas with circular movements twice a day for 14 days. The sensorial irritation test (pinching, burning, and itching) was carried out with the application of capsaicin at 3 × 10−4
% for 5 min [36
]. After the testing period, the authors verified that the group treated with the formulation containing bPOMC had fewer irritation sensations when compared to the control group, further indicating that biomimetic peptides, such as bPOMC, when used in skin formulations, can significantly reduce symptoms from contact dermatitis, which is an issue for several consumers of cosmetics and topic formulations [36
This compound is often associated with liposomes, made of a complex of phyto-endorphins responsible for stimulating fibroblast and keratinocyte proliferation, resulting in wrinkle attenuation and increased cell renewal, revitalization, and hydration [37
]. There are still no conclusive studies on the efficacy of this peptide. It is commercialized by Mibelle AG Biochemistry, and its INCI name is lecithin (and) Vitex agnus-castus extract (and) glycerin (and) ascorbyl tetraisopalmitate (and) tocopherol (and) olus oil / vegetable oil (and) cyclodextrin (and) alcohol (and) water [37
6. Safety Assessment of Bioactive Peptides Used in Cosmetics
Some bioactive peptides have already been studied regarding their safety both in vitro and in vivo. According to the FDA (Food and Drug Administration), up to 2012, palmitoyl-like peptides have been the most extensively tested molecules regarding safety so far, as they are also commercialized in cosmetic products [38
The bioactive acetyl hexapeptide-3 has been studied to some extent. Maia Campos and collaborators (2014) [39
] evaluated the safety of this peptide by making use of the primary skin irritation test and the patch test. They describe having used a hypoallergenic adhesive tape (50 mm2
area) applied a single time at occlusive conditions to the dorsal area of 27 volunteers (aged between 20 to 59 years) of phototypes II and IV. After 48 h, the tape was removed and the visual evaluation of the result was performed when the erythema was no longer was perceptible; no irritation reactions were caused after 48 h of occlusive contact. The research group of Blanes-Mira and collaborators (2002) [26
], also demonstrated by means of the skin irritation test, reported that the bioactive acetyl hexapeptide-3 is safe to use in an analysis that used botulinum neurotoxin as a control.
Another study of skin irritation carried out with peptide GHK-Cu at a volume of 0.5 mL in an area of 6 cm2
using three male rabbits and a covering tape for 24 h, with readings conducted at 24 and 72 h, demonstrated that this active component is not a skin irritant under the tested conditions (PII = 0.3) [40
Bioactive peptides are becoming increasingly popular in the research and development of cosmetic formulations aimed at treating damaged and dysfunctional skin. Several companies such as PharmaSpecial®, Galena®, Biotec®, Lipotec®, and Silab® are investing in technologically innovative bioactive peptides, focusing on signal peptides and neurotransmitter inhibitor peptides. Bioactive peptides amount to 10% of all sales of pharmaceutical companies.
Any cosmetic products which contain bioactive peptides in their formulations must be submitted to efficacy and safety tests in order to be approved by the National Health Surveillance Agency (ANVISA) and thus allowed to be commercialized. However, there is a lack of published studies on such peptides; the most commonly studied peptides are synthetized from palmitoyl, such as palmitoyl oligopeptide, palmitoyl pentapeptide-4, and palmitoyl tetrapeptide-7, and such studies are generally focused on wrinkle attenuation and skin filling.
It was observed that the majority of research studies are focused on the development of anti-aging actives, and there is still room for research to be carried out to evaluate other functions of these actives. Studies reporting on the efficacy of bioactive peptides with specific functions and clarifying their mechanisms of action, mostly regarding their actions upon the attenuation of stretch marks and cellulites, are few, which makes it difficult to search for specific functions of bioactive peptides.