Tripeptide-1 and Its Potential Interactions with Dermal Cells

Tripeptide-1 is a tripeptide that is also referred to as GHK Basic, stemming from its sequence of Gly-His-Lys (GHK). It is purportedly found as a sequence in type 1 collagen and may signal that there is collagen breakdown to various dermal cells. Consequently, this may result in increased collagen synthesis, reduced breakdown of the remaining or new collagen fibers, and other potential relevance related to dermal cell protection against UV light and various oxidative radicals. Thus, the peptide is researched in the context of dermal cell integrity, protection from collagen breakdown, and UV light damage.

 

Research

Tripeptide-1 Structure and Potential Mechanisms

Tripeptide-1 is a peptide that was first characterized by a team of researchers led by Pickart et al.⁽¹⁾ According to the scientists, its GHK sequence mimics that of an endogenous fragment that dermal cells such as fibroblasts and keratinocytes, along with immune cells, are thought to release.

This GHK sequence is released as a product when there is a factor leading to collagen breakdown, and it may act as a signal for cellular damage that may upregulate the synthesis of new collagen. Specifically, the α2(I) chain of type I collagen contains a GHK motif at residues 853 to 855, tucked within the triple-helical region, and it may be released when broken down to stimulate fibroblasts to produce new collagen.

Dermal fibroblasts are considered to be the main type of dermal cell producing collagen. Research by Maquart et al. suggests that exposing fibroblasts to Tripeptide-1 may lead to an apparent rise in type I collagen output.⁽²⁾ Тhey proposed that the GHK sequence may carry this stimulating signal, probably by gathering trace copper already present in the medium or shuttling endogenous metal across the membrane.

In models of cellular and collagen damage, the GHK sequence might be liberated by proteases, specifically at a site of injury to encourage repair. Specifically, the researchers commented that there appears to be a “presence of a Tripeptide-1 triplet in the alpha 2(I) chain of type I collagen”. In addition, the researchers note that GHK appears to have affinity for copper, and posit that the resulting copper-peptide complex may engage metal-dependent enzymes tied to matrix remodeling and redox balance. Furthermore, Tripeptide-1 is described as a candidate signal for dermal cell regeneration that may help reduce oxidative stress and inflammatory activity in laboratory models.

Tripeptide-1 Potential to Restrain Collagen Breakdown

Research in mammalian injury models also suggests that Tripeptide-1 may have the potential to not only stimulate collagen synthesis, but also help modulate collagen breakdown, possibly by decreasing it. Specifically, research by Canapp et al. studied injury models that expressed elevated pro-MMP-2 and pro-MMP-9, which are considered indicators linked to collagen breakdown.⁽³⁾ While metalloproteinases may aid cell migration and clearing denatured proteins, if their activity runs too high, they may strip away newly deposited collagen.

Based on the researchers’ observations, exposure to the Tripeptide-1 was associated with lower concentrations of both the precursor and active forms of these enzymes. By trimming the pool of active MMPs, the peptide may slow matrix turnover to a pace that allows more orderly collagen deposition and maturation.

The authors posited that the complex may dampen protease transcription, hasten the mitigation of synthesis, or sequester the copper ions that would otherwise help switch MMPs on. Apart from collagen, this may also help other important matrix proteins such as fibronectin and laminin to become less prone to premature degradation.

These observations have been linked to better-supported recovery in dermal cell injury models in research by Mulder et al.⁽⁴⁾ Specifically, the authors suggested that applying Tripeptide-1 may coordinate copper ions towards proteins such as fibrin, fibronectin, and latent growth factors and this promote new vessel formation in dermal wound models.

When the peptide was introduced, tissue recovery reportedly reached roughly 98 percent, against about 61 percent in unexposed controls. The same work noted a lower rate of bacterial presence in exposed models, on the order of 7 percent compared with 34 percent in controls. The authors posited that the peptide may act indirectly, either by speeding closure so opportunistic microbes have a narrower window or by adjusting how local immune cells are recruited.

Tripeptide-1 Protection of Dermal Cells from UV light

Laboratory data from Cebrián et al. suggest that Tripeptide-1 may aid the defenses of dermal cells from ultraviolet B damage by acting as a carbonyl scavenger.⁽⁵⁾ Ultraviolet B is posited to raise reactive carbonyl species inside dermal cells while depleting an antioxidant called glutathione that is considered to help detoxify these cells. As glutathione falls, reactive carbonyls may build up and form adducts with essential proteins, driving increased cellular damage and loss of integrity.

The team experimented with Tripeptide-1 against two aggressive aldehydes that may accumulate in UVB-exposed dermal cells, namely 4-hydroxy-2-nonenal and acrolein. Mixing either aldehyde with the peptide apparently lowered the amount of free aldehyde and the protein-damaging adducts it usually forms.

According to the observations, the peptide appears to sacrifice itself, binding the carbonyls before they may reach any dermal proteins. Relative to carnosine, a familiar aldehyde scavenger, the peptide looked somewhat weaker against 4-hydroxy-2-nonenal yet stronger against acrolein. The protective pattern was apparently carried into models of keratinocyte cultures, which normally clear 4-hydroxy-2-nonenal by joining it to glutathione. A moderate ultraviolet B exposure may strip the glutathione reserve of these cells and leave the monolayer exposed. Under those conditions, an added aldehyde may tend to destroy large areas of the cell layer.

Yet, cultures pre-exposed to the peptide apparently stayed intact and produced fewer aldehyde-glutathione conjugates. The researchers concluded that based on these observations, Tripeptide-1 may indeed “mitigate the damage of RCS and UVB radiation and [may] act as a scavenger of specific RCS (HNE, acrolein) and [may] mitigate glycation of protein, avoiding the formation of advanced glycation end-products.”

Tripeptide-1 Potential for Oxidative Stress and Inflammatory Signaling Modulation

Experiments by Sakuma et al. have further examined the potential of Tripeptide-1 against free radicals, and their observations suggest that the peptide may lower the levels of molecules like hydroxyl radicals by about 47% and tert-butyl peroxyl radicals by about 30%.⁽⁶⁾

The same actions were not observed when the three amino acids which make up Tripeptide-1 were added in a mixture, suggesting that the specific configuration of Tripeptide-1 may carry this potential. More specifically, this implies that the intact geometry of the tripeptide, or perhaps its ability to bind transition metals, forms the active motif.

Work by Miller et al. also suggested that the peptide may lessen iron-driven oxidative stress in damaged tissue.⁽⁷⁾ In their observations, the peptide seemed to bind the ferritin channels involved in iron release. It apparently curbed the escape of iron ions by around 87 percent. For dermal cells, limiting the pool of loose, reactive iron may translate into less catalytic fuel for the radical reactions that follow ultraviolet or mechanical injury.

An experiment by Park et al. also suggested that the peptide may lower the oxidative stress caused by endogenous factors such as immune cells.⁽⁸⁾ Such cells normally unleash a burst of reactive oxygen species along with pro-inflammatory signals such as TNF-α and IL-6. With the peptide present, intracellular reactive oxygen species apparently fell, superoxide dismutase activity appeared to recover toward normal, and the cytokine surge was substantially blunted.

According to the researchers, Tripeptide-1 may have the potential to keep the transcription factor NF-κB p65 out of the nucleus and to block a key activating phosphorylation on that same subunit. It also seemed to lower activation of the p38 MAP-kinase pathway and, to a smaller degree, JNK, while leaving the ERK branch alone. With these switches turned down, exposed cells were posited to generate fewer inflammatory mediators, alongside higher superoxide dismutase activity and more glutathione.

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References:

1. Pickart L, Vasquez-Soltero JM, Margolina A. GHK Peptide as a Natural Modulator of Multiple Cellular Pathways in Skin Regeneration. Biomed Res Int. 2015;2015:648108. doi: 10.1155/2015/648108. Epub 2015 Jul 7. PMID: 26236730; PMCID: PMC4508379.
2. Maquart FX, Pickart L, Laurent M, Gillery P, Monboisse JC, Borel JP. Stimulation of collagen synthesis in fibroblast cultures by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+. FEBS Lett. 1988 Oct 10;238(2):343-6. doi: 10.1016/0014-5793(88)80509-x. PMID: 3169264.
3. Canapp SO Jr, Farese JP, Schultz GS, Gowda S, Ishak AM, Swaim SF, Vangilder J, Lee-Ambrose L, Martin FG. The effect of topical tripeptide-copper complex on the healing of ischemic open wounds. Vet Surg. 2003 Nov-Dec;32(6):515-23. doi: 10.1111/j.1532-950x.2003.00515.x. PMID: 14648529.
4. Mulder GD, Patt LM, Sanders L, Rosenstock J, Altman MI, Hanley ME, Duncan GW. Enhanced healing of ulcers in patients with diabetes by topical treatment with glycyl-l-histidyl-l-lysine copper. Wound Repair Regen. 1994 Oct;2(4):259-69. doi: 10.1046/j.1524-475X.1994.20406.x. PMID: 17147644.
5. Cebrián J, Messeguer A, Facino RM, García Antón JM. New anti-RNS and -RCS products for cosmetic treatment. Int J Cosmet Sci. 2005 Oct;27(5):271-8. PMID: 18492138. https://doi.org/10.1111/j.1467-2494.2005.00279.x
6. Sakuma S, Ishimura M, Yuba Y, Itoh Y, Fujimoto Y. The peptide glycyl-L-histidyl-L-lysine is an endogenous antioxidant in living organisms, possibly by diminishing hydroxyl and peroxyl radicals. Int J Physiol Pathophysiol Pharmacol. 2018 Sep 15;10(3):132-138. PMID: 30364550; PMCID: PMC6199975.
7. Miller TR, Wagner JD, Baack BR, Eisbach KJ. Effects of topical copper tripeptide complex on CO2 laser-resurfaced skin. Arch Facial Plast Surg. 2006 Jul-Aug;8(4):252-9. doi: 10.1001/archfaci.8.4.252. PMID: 16847173.
8. Park JR, Lee H, Kim SI, Yang SR. The tripeptide GHK-Cu complex ameliorates lipopolysaccharide-induced acute lung injury in mice. Oncotarget. 2016 Sep 6;7(36):58405-58417. doi: 10.18632/oncotarget.11168. PMID: 27517151; PMCID: PMC5295439.