Tripeptide-3 Actions on Muscular Tissue Contraction and Dermal Topography

Tripeptide-3 (often referred to as Syn-AKE) is a synthetic compound that may mimic one of the actions of waglerin-1, a 22-amino acid peptide found in the venom of the Temple Viper.⁽¹⁾⁽²⁾ Structurally, Tripeptide-3 consists of β-alanyl–L-prolyl–3-aminomethyl-L-alanine benzyl amide acetic acid, and it is thought to selectively replicate waglerin-1’s potential to relax muscle cells by blocking their acetylcholine receptors at the neuromuscular junction. Unlike the full-length waglerin-1, which may have multiple biological interactions with various outcomes, Tripeptide-3 appears to target only the muscular nicotinic acetylcholine receptor (mnAChR), preventing sodium ion influx and thereby inhibiting muscle cell contraction.⁽³⁾

The peptide’s actions as a potential muscular nicotinic acetylcholine receptor antagonist may prove relevant to research in neuromuscular physiology. It may be of interest to researchers as a model compound to study how selective blockade of acetylcholine receptors might influence muscular tissue function in vitro and serve as a lead structure for designing new neuromuscular agents. Currently, research on Tripeptide-3 has specifically focused on its potential actions on the contraction of facial muscular tissue and the appearance of the dermatological tissues above, including wrinkles.

 

Research

Tripeptide-3 (Syn-AKE) and Nicotinic Acetylcholine Receptors

Similarly to the mechanisms revealed by Molles et al. on waglerin-1, Tripeptide-3 appears to block the nicotinic acetylcholine receptors (nAChRs) by competing with acetylcholine (ACh) for binding at specific sites on the receptor.⁽²⁾ Nicotinic acetylcholine receptors are ion channels that open when ACh binds, allowing ions to flow through and trigger muscular tissue contraction or nerve signaling. Tripeptide-3 may bind to these receptors, particularly at a site called the R- R-interface, with a stronger affinity than ACh in this specific location. When Tripeptide-3 may bind to the R- interface, it appears to physically block ACh from attaching to the receptor. Without ACh binding, the receptor may not open its ion channel, and the signal transmission process is interrupted. It is posited that Tripeptide-3 prefers the R- interface over other binding sites on the receptor due to specific amino acids in the subunit, such as Asp-173, Gly-57, and Tyr-115. These residues may create a favorable environment for Tripeptide-3 to bind tightly. Asp-173, in particular, seems to play a key role because it is part of a unique structural feature not found in other related proteins.

As mentioned by Munawar et al. and Reddy et al., the potential interaction between Tripeptide-3 and the nicotinic acetylcholine receptors appears to be reversible, as if the concentration of ACh increases significantly, it may outcompete Wtx-1 and displace it from the binding site.⁽⁴⁾⁽⁵⁾ This mechanism also appears to be similar to the interaction between the receptors and waglerin-1. At the same time, Tripeptide-3 appears to be active solely towards the nicotinic acetylcholine receptors and does not interact with other receptors, while waglerin-1 may also interact with γ-aminobutyric acid (GABA) signaling and induce undesired laboratory research outcomes.

Tripeptide-3 (Syn-AKE) and Muscle Cell Contractions

Without anything to block the ACh signaling, the acetylcholine released from nerve cells may bind to the nicotinic acetylcholine receptors on muscle cells and induce a conformational change in the receptor, causing the central ion channel to open. This may allow sodium ions (Na⁺) to flow into the muscle cell and potassium ions (K⁺) to flow out, though the influx of Na⁺ is the dominant action. The influx of Na⁺ creates a local depolarization of the muscle cell membrane at the neuromuscular junction. This depolarization is referred to as the end-plate potential (EPP). If the EPP is strong enough, it triggers the opening of voltage-gated sodium channels in the surrounding muscle cell membrane.

The opening of voltage-gated sodium channels initiates an action potential, which is a rapid and self-propagating wave of depolarization that spreads across the entire muscle cell membrane. This triggers a series of reactions inside muscle cells that appear to cause muscle cell contraction. By blocking the binding of ACh specifically to the nicotinic acetylcholine receptors of muscle cells, Tripeptide-3 may effectively inhibit muscle cell contractions. According to in vitro research by Gorouhi et al., within just 2 hours of experimentation, the peptide “was able to reduce the frequency of innervated muscle cell contractions by 82%”⁽⁶⁾. Therefore, it appears that the potential of Tripeptide-3 is rapid and may be targeted specifically towards muscle cells.

Tripeptide-3 (Syn-AKE) and Dermal Topography

By apparently reducing muscular tissue contraction, Tripeptide-3 may also affect the topography of overlying dermatological tissues. In dermal models that appear to exert wrinkling in the stratum corneum, it has been suggested that Tripeptide-3 may exhibit both immediate and sustained positive impacts on dermal topography. Specifically, by inhibiting the contraction of underlying muscle cells, the peptide may diminish dermal wrinkle depth soon after exposure. Moreover, research by Reddy et al. and Pai et al. suggests that the dermal smoothing potential of the peptide may gradually increase after repeated experimentation on the same models and reach more than 50% after 4 weeks.

Researchers commented that the peptide may have “[indicated] up to a 52% reduction in the appearance of wrinkle size” at 4% concentration in just 4 weeks of repeated experimentation. Reducing wrinkling may support the dermal layer’s barrier function and reduce transepidermal water loss (TEWL), potentially leading to better-supported hydration retention. Wrinkles create micro-irregularities on the dermis’ topography surface, which may compromise the integrity of the stratum corneum, which is the outermost layer responsible for retaining moisture. By smoothing the dermal layer and minimizing these irregularities, this barrier function may become more potent at mitigating water evaporation.

You can find Tripeptide-3 (Syn-AKE) for sale with 99% purity, on our website (available for research use only).

NOTE: These products are intended for laboratory research use only. This peptide is not intended for personal use. Please review and adhere to our Terms and Conditions before ordering.

 

References:

1. Balaev, A. N., Okhmanovich, K. A., & Osipov, V. N. (2014). A shortened, protecting group free, synthesis of the anti-wrinkle venom analogue Syn-Ake® exploiting an optimized Hofmann-type rearrangement. Tetrahedron Letters, 55(42), 5745-5747.
2. Molles, B. E., Tsigelny, I., Nguyen, P. D., Gao, S. X., Sine, S. M., & Taylor, P. (2002). Residues in the epsilon subunit of the nicotinic acetylcholine receptor interact to confer selectivity of waglerin-1 for the alpha-epsilon subunit interface site. Biochemistry, 41(25), 7895–7906. https://doi.org/10.1021/bi025732d
3. Schagen, S. K. (2017). Topical peptide treatments with effective anti-aging results. Cosmetics, 4(2), 16.
4. Munawar, A., Ali, S. A., Akrem, A., & Betzel, C. (2018). Snake venom peptides: Tools of biodiscovery. Toxins, 10(11), 474.
5. Reddy, B., Jow, T., & Hantash, B. M. (2012). Bioactive oligopeptides in dermatology: Part I. Experimental dermatology, 21(8), 563–568. https://doi.org/10.1111/j.1600-0625.2012.01528.x
6. Gorouhi, F., & Maibach, H. I. (2009). Role of topical peptides in preventing or treating aged skin. International journal of cosmetic science, 31(5), 327–345. https://doi.org/10.1111/j.1468-2494.2009.00490.x
7. Pai, V. V., Bhandari, P., & Shukla, P. (2017). Topical peptides as cosmeceuticals. Indian Journal of Dermatology, Venereology and Leprology, 83, 9.
8. Reddy, B. Y., Jow, T., & Hantash, B. M. (2012). Bioactive oligopeptides in dermatology: Part II. Experimental dermatology, 21(8), 569–575. https://doi.org/10.1111/j.1600-0625.2012.01527.x