CJC-1295 DAC, also referred to as DAC: GRF or long-acting growth hormone-releasing hormone (GHRH) analog, is a synthetic 29-amino acid peptide derived from the endogenous GHRH sequence.1 It represents a tetrasubstituted analog, incorporating D-Ala, Gln, Ala, and Leu substitutions at positions 2, 8, 15, and 27, respectively. These targeted modifications are intended to support molecular stability and receptor binding affinity while preserving the peptide’s ability to stimulate somatotroph cells of the anterior pituitary.

The peptide was originally developed by ConjuChem, a Canadian biotechnology company, in the mid-2000s.^[2] Initial research efforts centered on exploring its potential to modulate growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels. The compound’s design incorporates a Drug Affinity Complex (DAC), a lysine-linked derivative of N-ε-3-maleimidopropionamide, which enables covalent attachment to plasma proteins such as serum albumin.

This molecular engineering substantially prolongs the peptide’s biological half-life, extending it from minutes (in the case of endogenous GHRH or Modified GRF 1-29) to approximately eight days, thereby facilitating sustained receptor interaction and prolonged GH secretory response. CJC-1295 DAC is recognized as the shortest functional analog of GHRH capable of inducing GH release. Research suggests that this analog maintains high receptor affinity while displaying better-supported pharmacokinetic stability compared to shorter GHRH fragments or non-DAC counterparts.

 

Mechanism of Action

CJC-1295 DAC is postulated to act through the endogenous growth hormone axis, mimicking the activity of endogenous GHRH. The peptide binds to GHRH receptors located on somatotroph cells within the anterior pituitary, initiating cyclic adenosine monophosphate (cAMP)-dependent intracellular signaling cascades. This process may activate protein kinase A (PKA), leading to better-supported transcription of GH-encoding genes and exocytotic release of stored GH vesicles.

Physiologically, GH secretion occurs in pulsatile bursts, governed by the interplay between GHRH and somatostatin (growth hormone-inhibiting hormone). Research suggests that analogs like CJC-1295 DAC may reinforce these pulsatile secretions by amplifying the stimulatory phase while maintaining an endogenous mitigatory rhythm.^[3] Furthermore, the peptide’s interaction with plasma proteins via the DAC moiety may create a slow-release depot, allowing for sustained receptor activation without overstimulation.

Studies also suggest that CJC-1295 DAC may function synergistically with ghrelin mimetics (e.g., GHRP-6 or Hexarelin), which act on separate ghrelin receptors to suppress somatostatin and support GHRH-driven GH release. This dual-pathway interaction might potentiate IGF-1 synthesis in hepatic tissues, contributing to downstream anabolic and lipolytic signaling pathways. Collectively, the biochemical design of CJC-1295 DAC, combining receptor-specific activity with plasma protein conjugation, appears to optimize both efficacy and stability within experimental models evaluating GH regulation and metabolic homeostasis.

 

Scientific Research and Studies

 

Experimental Findings and Endocrine Activity of CJC-1295 DAC

In 2006, researchers conducted two controlled clinical studies to explore the potential endocrine implications of CJC-1295 DAC. The first involved a single ascending concentration design, while the second examined repeated exposure at a fixed concentration.^[4] Across both investigations, exposure to CJC-1295 DAC was associated with a measurable increase in circulating growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels compared to baseline models.

The observed rise in IGF-1 is theorized to result from better-supported GH production, which may bind to hepatic GH receptors, initiating downstream activation of the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway. This cascade potentially leads to phosphorylation of STAT proteins and their translocation to the nucleus, where they may engage specific DNA response elements to promote IGF-1 gene transcription.

Experimental data suggest that exposure to CJC-1295 DAC may result in 2- to 10-fold elevations in GH persisting for up to six days, while IGF-1 levels may increase 1.5- to 3-fold and remain above baseline for approximately 9-11 days. In repeated-exposure models, these elevations reportedly persisted for up to 28 days, suggesting a possible cumulative implication on the GH-IGF-1 axis, suggesting “the potential [implications] of CJC-1295 as a [helpful] agent.”^[4]

 

Analysis of Mammalian Growth Hormone Pulsatility, Receptor Pathway Activation

A separate 2006 investigation assessed the peptide’s support for GH pulsatility following a single peptide introduction.^[5] Findings reported an approximate 50% increase in mean GH secretion and a similar elevation in IGF-1 levels compared to baseline, with peak GH concentrations reported to rise as much as 7.5-fold.

At the molecular level, CJC-1295 DAC is believed to interact with the growth hormone-releasing hormone (GHRH) receptor, a G-protein-coupled receptor located on somatotroph cells in the anterior pituitary. This receptor engagement may activate G-protein subunits, promoting the synthesis of intracellular second messengers such as cyclic adenosine monophosphate (cAMP) and inositol trisphosphate (IP3).

These messengers, in turn, are thought to activate protein kinases, which phosphorylate transcription regulators involved in GH gene expression.^[6] This multi-step signaling cascade may therefore support GH synthesis and release, aligning with the peptide’s observed ability to sustain elevated GH output within mammalian research models.

 

Preclinical Assessment in GHRH-Deficient Murine Models

Further investigations were carried out using murine models lacking the GHRH gene (GHRHKO) to evaluate the anabolic potential of CJC-1295 DAC. In these studies, subjects received either daily or intermittent peptide exposure, while control groups received a placebo. Findings suggest that daily exposure nearly normalized growth profiles in GHRHKO models, while exposure every two to three days produced intermediate implications, suggesting a frequency-dependent response.

CJC-1295 DAC was associated with increased lean muscular tissue mass preservation and reduced fat accumulation, potentially indicating support for mass of mammalian models through GH-mediated anabolic pathways. Additionally, the peptide appeared to increase pituitary total RNA and GH mRNA levels, suggesting a rise in somatotroph cell proliferation.

Immunohistochemical observations have supported this hypothesis, revealing better-supported somatotroph density within the anterior pituitary following peptide exposure. Collectively, these preclinical findings imply that CJC-1295 DAC may modulate GH synthesis, pituitary cellular activity, and tissue growth dynamics through mechanisms consistent with its classification as a long-acting GHRH analog.

 

Supplementary Investigations and Analytical Evaluations

In 2005, a clinical investigation^[8] was initiated to examine the potential endocrine and metabolic activity of CJC-1295 DAC in models representing HIV-associated visceral adiposity. The planned study design involved peptide exposure over three months, followed by a six-week observational phase to monitor post-exposure outcomes. However, this investigation was discontinued during the recruitment phase, and no validated findings or results were reported from the trial.

Subsequently, a 2009 analytical study conducted by researchers from the Norwegian Doping Control Laboratory and the School of Pharmacy aimed to identify the biochemical nature of an unfamiliar compound submitted for substance verification. Analytical characterization reported that the peptide “CJC-1295 DAC is a releasing factor for growth hormone.”^[1]

 

Pharmacokinetic Modifications and Half-Life Extension

CJC-1295 DAC incorporates a molecular engineering platform referred to as the Drug Affinity Complex (DAC), designed to prolong peptide stability through plasma protein binding.^[1] Endogenous growth hormone-releasing hormone (GHRH) is characterized by a brief biological half-life of approximately 7 minutes, largely due to rapid enzymatic degradation.

In contrast, CJC-1295 without DAC, also referred to as Modified GRF (1–29), exhibits a longer half-life of about 30 minutes, attributed to targeted amino acid substitutions within its 29-residue fragment. Structural modification of four amino acid positions, 2, 8, 15, and 27, is theorized to support the peptide’s resistance to dipeptidyl peptidase-4 (DPP-IV) degradation and oxidative instability. These substitutions include:

•         Position 2: L-alanine replaced by D-alanine, potentially supporting enzymatic stability.
•         Position 8: Asparagine replaced by glutamine, which may reduce susceptibility to deamidation and amide hydrolysis.
•         Position 15: Glycine replaced by alanine, a substitution hypothesized to support greater receptor binding efficiency.
•         Position 27: Methionine replaced by leucine, potentially minimizing oxidative reactions and preserving peptide integrity.

The addition of the DAC moiety, formed by conjugation of a lysine residue to N-ε-3-maleimidopropionamide, further extends the circulating half-life through reversible binding to serum albumin. This binding mechanism may create slow-release implications, resulting in a prolonged biological half-life estimated between 6 and 8 days ^[9] Collectively, these molecular adaptations appear to optimize both pharmacokinetic stability and functional persistence under laboratory conditions.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing. Bodily introduction of any sort is strictly prohibited by law. All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

 

References:

1. Henninge J, Pepaj M, Hullstein I, Hemmersbach P. Identification of CJC-1295, a growth-hormone-releasing peptide, in an unknown pharmaceutical preparation. Drug Test Anal. 2010 Nov-Dec;2(11-12):647-50. doi: 10.1002/dta.233. Epub 2010 Dec 10. PMID: 21204297. https://pubmed.ncbi.nlm.nih.gov/21204297/
2. Alba M, Fintini D, Sagazio A, Lawrence B, Castaigne JP, Frohman LA, Salvatori R. Once-daily administration of CJC-1295, a long-acting growth hormone-releasing hormone (GHRH) analog, normalizes growth in the GHRH knockout mouse. Am J Physiol Endocrinol Metab. 2006 Dec;291(6):E1290-4. doi: 10.1152/ajpendo.00201.2006. Epub 2006 Jul 5. PMID: 16822960. https://pubmed.ncbi.nlm.nih.gov/16822960/
3. Sinha DK, Balasubramanian A, Tatem AJ, Rivera-Mirabal J, Yu J, Kovac J, Pastuszak AW, Lipshultz LI. Beyond the androgen receptor: the role of growth hormone secretagogues in the modern management of body composition in hypogonadal males. Transl Androl Urol. 2020 Mar;9(Suppl 2):S149-S159. doi: 10.21037/tau.2019.11.30. PMID: 32257855; PMCID: PMC7108996. https://pubmed.ncbi.nlm.nih.gov/32257855/
4. Teichman SL, Neale A, Lawrence B, Gagnon C, Castaigne JP, Frohman LA. Prolonged stimulation of growth hormone (GH) and insulin-like growth factor I secretion by CJC-1295, a long-acting analog of GH-releasing hormone, in healthy adults. J Clin Endocrinol Metab. 2006 Mar;91(3):799-805. doi: 10.1210/jc.2005-1536. Epub 2005 Dec 13. PMID: 16352683. https://pubmed.ncbi.nlm.nih.gov/16352683/
5. Ionescu M, Frohman LA. Pulsatile secretion of growth hormone (GH) persists during continuous stimulation by CJC-1295, a long-acting GH-releasing hormone analog. J Clin Endocrinol Metab. 2006 Dec;91(12):4792-7. doi: 10.1210/jc.2006-1702. Epub 2006 Oct 3. PMID: 17018654. https://pubmed.ncbi.nlm.nih.gov/17018654/
6. Newton, A. C., Bootman, M. D., & Scott, J. D. (2016). Second Messengers. Cold Spring Harbor perspectives in biology, 8(8), a005926. https://doi.org/10.1101/cshperspect.a005926
7. Alba M, Fintini D, Sagazio A, Lawrence B, Castaigne JP, Frohman LA, Salvatori R. Once-daily administration of CJC-1295, a long-acting growth hormone-releasing hormone (GHRH) analog, normalizes growth in the GHRH knockout mouse. Am J Physiol Endocrinol Metab. 2006 Dec;291(6):E1290-4. doi: 10.1152/ajpendo.00201.2006. Epub 2006 Jul 5. PMID: 16822960. https://pubmed.ncbi.nlm.nih.gov/16822960/
8. ClinicalTrials.gov, A service of the US National Institutes of Health. Available at: http://clinicaltrials.gov/ct2/show/NCT00267527
9. Van Hout MC, Hearne E. Netnography of Female Use of the Synthetic Growth Hormone CJC-1295: Pulses and Potions. Subst Use Misuse. 2016 Jan 2;51(1):73-84. doi: 10.3109/10826084.2015.1082595. Epub 2016 Jan 15. PMID: 26771670. https://pubmed.ncbi.nlm.nih.gov/26771670/

Modified GRF 1-29, also referred to as CJC 1295 without DAC or the tetra-substituted GRF 1-29, is a synthetic analogue of growth hormone releasing hormone. It contains the first 29 amino acids of endogenous GHRH, which early studies identified as the minimal sequence capable of retaining the functional characteristics of the full 44 amino acid hormone.^[1][2] The original GRF 1-29 fragment, also referred to as Sermorelin, may indicate rapid enzymatic degradation and a short biological lifespan.

To support overall stability, four amino acid substitutions were introduced at positions 2, 8, 15, and 27.^[3] These substitutions were intended to reduce proteolytic cleavage, limit oxidative changes, decrease spontaneous rearrangements, and increase resistance to hydrolysis.

The modified fragment, later termed Modified GRF 1-29, preserves the structural domains believed to be required for GHRH receptor binding while indicating potentially increased persistence in experimental systems. Its development traces back to work in the 1980s on truncated GHRH derivatives. Research has explored its potential involvement in metabolic and regenerative pathways, though findings remain model-dependent.

 

Mechanism of Action

Modified GRF 1-29 is engineered to bind growth hormone releasing hormone receptors, which are class B G protein-coupled receptors located in the anterior pituitary. The 29 amino acid sequence reflects the N-terminal region associated with receptor activation in endogenous GHRH.^[4] The structural substitutions are theorized to support receptor interaction and reduce degradation, supporting more sustained signaling.

Receptor engagement is proposed to activate adenylate cyclase through Gs protein coupling, increasing intracellular cyclic adenosine monophosphate. This signaling route may interact with protein kinase A pathways involved in growth hormone synthesis and vesicular release. Studies conducted in laboratory settings suggest that stabilized GHRH fragments may support pulsatile secretion patterns, although temporal dynamics vary across studies.

Reported downstream pathways include those linked to tissue repair, extracellular matrix modulation, energy metabolism, and musculoskeletal adaptation. Additional research has examined possible roles in glucose regulation and immune-related processes. These observations remain dependent on experimental context and peptide stability.

 

Scientific Research and Studies

 

Regulatory Modulation of the Growth Hormone Axis by Modified GRF 1-29

Research on fully tetrasubstituted GRF 1-29, often referenced as CJC 1295 without DAC, remains limited. Available studies have instead examined related analogs of GRF 1-29 with partial substitutions. One study by Khorram and colleagues evaluated a Modified GRF 1-29 construct and reported findings that might offer indirect insight into the behavior of tetrasubstituted variants.

The study^[5] suggested that Modified GRF 1-29 may support growth hormone pulsatility through interactions with somatotroph cells in the anterior pituitary. Average growth hormone output over twelve hours may indicate an approximate increase of 70% to 107%, suggesting a potential interaction with endogenous pulsatile dynamics. Parallel changes in insulin-like growth factor 1 were also observed, with concentrations rising by roughly 28%. These findings may reflect upstream modulation of the growth hormone IGF 1 axis.

The researchers also recorded changes in tissue characteristics. Dermal thickness increased in association with elevated growth hormone and IGF 1 activity. This pattern might relate to anabolic signaling in dermal fibroblasts and extracellular matrix-producing cell types. Muscle hypertrophy in mammalian models was also noted, and the net gain in lean muscular tissue suggested a possible anabolic response. The biological mechanisms driving these observations were not fully defined, and the relationship between peptide structure, receptor engagement, and downstream intracellular signaling remains an open area for further study.

Overall, the reported data suggest that modified GRF 1-29 analogs may participate in regulatory pathways connected to growth hormone and IGF 1 secretion. Future experiments focused specifically on tetrasubstituted GRF 1-29 will be required to clarify its mechanistic profile and potential research implications.

 

Receptor Level Interactions between Modified GRF 1-29 and Pituitary Signaling Pathways

Modified GRF 1-29 is thought to interact with the growth hormone releasing hormone receptor located on anterior pituitary cells. This interaction may involve engagement with specific receptor binding domains, which might induce subtle conformational adjustments in the receptor structure. Such changes might initiate intracellular signaling events consistent with G protein-coupled receptor activation.^[6]

Once the receptor undergoes this conformational shift, associated G proteins on the intracellular surface may become activated. These G proteins may stimulate the formation of secondary messengers such as cAMP or IP3. These molecules are considered intermediary signaling mediators that may amplify intracellular responses.^[7] In particular, cAMP may activate protein kinases that participate in phosphorylation reactions involving designated intracellular targets.

Protein kinases are implicated in the regulation of diverse cellular processes. Their activation may lead to phosphorylation of transcription factors that support gene expression. Phosphorylated transcription factors may enter the nucleus and modify the transcription of genes associated with growth hormone synthesis and secretion.

As a result, the cumulative molecular activity triggered by Modified GRF 1-29 may support the fusion of growth hormone-containing vesicles with the plasma membrane. This vesicular fusion may allow the extracellular release of growth hormone from pituitary cells and support downstream physiological signaling pathways.

 

Intestinal and Enteric Receptor Activity Linked to Modified GRF 1-29

Experimental and pre-clinical studies have suggested that growth hormone releasing hormone analogs may support gastrointestinal physiology. Peptides such as Modified GRF 1-29, as GHRH analogs, are under investigation to determine whether they might modulate bowel motility and smooth muscle function.

Some branches of primate research suggest that CJC 1295 without DAC interacts with VPAC1 receptors on gastric smooth muscle cells. This receptor engagement may interact with contractile activity and support mammalian bowel motility, which may have implications for gastrointestinal disorders such as constipation. Prior work has noted that species-specific differences are substantial, emphasizing the importance of receptor affinity assessments in mammalian cells or closely related species to assess translational potential.

Scientists believe that these studies “[indicate] significant species differences [may] exist for possible therapeutic peptide agonists of the VIP/PACAP/GRF receptor family and that it is essential that receptor affinity assessments be performed in [mammalian] cells or from a closely related species.”^[7]

 

Cardiac Indicators in Models Exposed to Modified GRF 1-29

Murine research^[9] suggested that Modified GRF 1-29 and related analogs might interact in some way with mammalian cardiac performance under post-strenuous or muscular overuse-causing activity conditions. Findings included potential support for heart rate, contractile function, and signals related to myocardial tissue repair, along with possible changes in ejection fraction. These observations are preliminary and require additional mechanistic study.

 

Clinical Studies Implying Interaction Between Growth Hormones and Thyroid

Clinical observations have suggested that thyroid hormone status may modulate growth hormone synthesis and secretion. In a study, 10 mammalian research models with primary hypothyroidism were analyzed. Fourteen research models of various levels of cellular age and overall function were examined before and after mammalian models undergo forms of thyroid hormone replacement.

Administration of CJC 1295 without DAC was associated with increased growth hormone responsiveness following thyroid replacement. These findings suggest that thyroid hormone availability may support somatotroph sensitivity to GHRH analogs, including tetrasubstituted GRF 1 29.

As per R Valcavi et al., “These data indicate that thyroid hormone replacement therapy [supports] the responsiveness of the somatotroph to GRF 1-29 in [mammalian research models] with primary hypothyroidism.” ^[10]

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing. Bodily introduction of any sort is strictly prohibited by law. All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

 

References:

1. National Center for Biotechnology Information (2025). PubChem Compound Summary for CID 91976842, CJC1295 Without DAC. https://pubchem.ncbi.nlm.nih.gov/compound/CJC1295-Without-DAC.
2. Clark RG, Robinson IC. Growth induced by pulsatile infusion of an amidated fragment of human growth hormone releasing factor in normal and GHRF-deficient rats. Nature. 1985 Mar 21-27;314(6008):281-3. doi: 10.1038/314281a0. PMID: 2858818. https://pubmed.ncbi.nlm.nih.gov/2858818/
3. Martin, B., Lopez de Maturana, R., Brenneman, R., Walent, T., Mattson, M. P., & Maudsley, S. (2005). Class II G protein-coupled receptors and their ligands in neuronal function and protection. Neuromolecular medicine, 7(1-2), 3–36. https://doi.org/10.1385/nmm:7:1-2:003
4. The Discovery of Growth Hormone-Releasing Hormone: An Update https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2826.2008.01740.x
5. Khorram, O., Laughlin, G. A., & Yen, S. S. (1997). Endocrine and metabolic effects of long-term administration of [Nle27]growth hormone-releasing hormone-(1-29)-NH2 in age-advanced men and women. The Journal of clinical endocrinology and metabolism, 82(5), 1472–1479. https://doi.org/10.1210/jcem.82.5.3943
6.  Newton, A. C., Bootman, M. D., & Scott, J. D. (2016). Second Messengers. Cold Spring Harbor perspectives in biology, 8(8), a005926. https://doi.org/10.1101/cshperspect.a005926
7. Ito T, Igarashi H, Pradhan TK, Hou W, Mantey SA, Taylor JE, Murphy WA, Coy DH, Jensen RT. GI side-effects of a possible therapeutic GRF analogue in monkeys are likely due to VIP receptor agonist activity. Peptides. 2001 Jul;22(7):1139-51. https://pubmed.ncbi.nlm.nih.gov/11445245/
8. Schally AV, Zhang X, Cai R, Hare JM, Granata R, Bartoli M. Actions and Potential Therapeutic Applications of Growth Hormone-Releasing Hormone Agonists. Endocrinology. 2019 Jul 1;160(7):1600-1612. https://pubmed.ncbi.nlm.nih.gov/31070727/
9. Sinha, D. K., Balasubramanian, A., Tatem, A. J., Rivera-Mirabal, J., Yu, J., Kovac, J., Pastuszak, A. W., & Lipshultz, L. I. (2020). Beyond the androgen receptor: the role of growth hormone secretagogues in the modern management of body composition in hypogonadal males. Translational andrology and urology, 9(Suppl 2), S149–S159. https://doi.org/10.21037/tau.2019.11.30
10. Valcavi R, Jordan V, Dieguez C, John R, Manicardi E, Portioli I, Rodriguez-Arnao MD, Gomez-Pan A, Hall R, Scanlon MF. Growth hormone responses to GRF 1-29 in patients with primary hypothyroidism before and during replacement therapy with thyroxine. Clin Endocrinol (Oxf). 1986 Jun;24(6):693-8. https://pubmed.ncbi.nlm.nih.gov/3098458/

Syn-Coll, also known as Palmitoyl Tripeptide-5 (Palmitoyl-Lys-Val-Lys)^[1], is a synthetic tripeptide developed to replicate the biological activity of thrombospondin-1 (TSP-1), an extracellular matrix glycoprotein considered to be involved in cellular signaling and structural maintenance.

Research suggests that the design of Syn-Coll was based on short peptide motifs within TSP-1. Specifically, the structure in TSP-1 that has been implicated in stimulating transforming growth factor beta (TGF-β), a regulatory cytokine central to extracellular matrix homeostasis.^[2] TGF-β is believed by researchers to influence fibroblast function, regulate extracellular matrix protein turnover, and contribute to postnatal tissue remodeling processes. By structurally mimicking the functional motifs of TSP-1, Syn-Coll may modulate signaling pathways associated with collagen synthesis and matrix stability.

 

Generalized Overview

Data from cell culture and animal studies suggests that Syn-Coll may stimulate fibroblast activity via increased TGF-β signaling. This signalling may increase the production of Type I and Type III collagen, which are considered to be the principal fibrillary collagens in dermal architecture.

Reports further suggest that Syn-Coll may exert a dual role in collagen homeostasis: promoting neocollagenesis while inhibiting degradation. The latter action is hypothesized to occur through downregulation of matrix metalloproteinase (MMP-1 and MMP-3), enzymes associated with collagen breakdown and extracellular matrix remodeling. The combination of enhanced collagen synthesis and reduced enzymatic degradation positions Syn-Coll as a peptide of interest in studies investigating extracellular matrix preservation and repair mechanisms.

 

Scientific Research and Studies

 

Syn-Coll Tripeptide and Potential Mechanisms of Wrinkle Attenuation

Research in controlled studies suggests that Syn-Coll tripeptide may influence skin cell surface morphology and wrinkle parameters. In one investigation utilizing PRIMOS surface topography, peptide-containing formulations suggested a concentration-dependent reduction in wrinkle depth when compared with placebo groups. Reports from this study^[3] hypothesized that Syn-Coll might exhibit several-fold greater activity in reducing wrinkle appearance relative to control formulations.

Additional studies involving delineated cohorts over extended durations (e.g., 84-day protocols) suggest that Syn-Coll may contribute to reductions in skin roughness and wrinkle measurements when compared with placebos or alternative peptide formulations. Reported data in such studies included reductions in wrinkle parameters in the range of approximately 12%.^[4]

Beyond modulation of collagen synthesis and matrix degradation, Syn-Coll tripeptide may exert action on skin barrier homeostasis. Findings suggest possible roles in reducing transepidermal water loss, thereby potentially supporting hydration retention.^[5] The peptide has been described in some studies as exhibiting humectant-like properties, enhancing water absorption and retention within the stratum corneum. Additional mechanisms may involve increasing surface lipid content, providing emollient activity, and contributing to partial occlusion and lubrication of the skin barrier.

Structural modifications of Syn-Coll have also been explored. For example, conjugation of an L-ascorbate moiety at the C-terminus (Pal-KVK-AA) has been investigated for its potential depigmenting activity. Experimental data suggests that such modifications may interfere with melanin biosynthesis, thereby influencing pigmentation processes associated with photo aging and oxidative stress. These findings highlight the broader scope of Syn-Coll research beyond wrinkle modulation, extending to pigmentation and barrier function pathways.

 

Syn-Coll Tripeptide and Regulation of Collagen Biosynthesis

Collagen represents a fundamental structural protein within the extracellular matrix (ECM), contributing to dermal integrity and connective tissue organization. Research suggests that Syn-Coll may influence collagen homeostasis by mimicking functional motifs of thrombospondin-1 (TSP-1).^[6] This mimicry is hypothesized to facilitate activation of transforming growth factor beta (TGF-β), a regulatory cytokine associated with extracellular matrix regulation.

Studies report that Syn-Coll may promote the activation of latent TGF-β, leading to “a persistent increase in steady-state amounts of type I and type III collagen and fibronectin mRNAs in normal dermal fibroblasts.”^[7] Reports also describe a sustained upregulation of messenger RNA transcripts for Type I collagen, Type III collagen, and fibronectin following TGF-β stimulation. Such findings suggest that the peptide may support neocollagenesis through indirect modulation of fibroblast activity.

Comparative investigations have also examined Syn-Coll relative to other synthetic peptides, such as Palmitoyl Pentapeptide. Data from these studies hypothesize that Syn-Coll may be associated with enhanced stimulation of Type I collagen synthesis, with some reports suggesting a greater relative effect, potentially up to 60% higher than Palmitoyl Pentapeptide under certain experimental conditions.

 

Syn-Coll Tripeptide and the Inhibition of Collagen-Degrading Enzymes

Matrix metalloproteinase (MMPs) are proteolytic enzymes that contribute to extracellular matrix turnover through degradation of structural proteins, including collagen. These enzymes are produced by dermal cells such as fibroblasts and may play essential roles in tissue remodeling and homeostasis. Dysregulated or excessive MMP activity, however, has been associated with accelerated collagen degradation and extracellular matrix destabilization. For example, MMP-1 is a collagenase that targets Type I collagen, while MMP-3 exhibits broader substrate specificity, cleaving multiple extracellular proteins such as collagens, fibronectin, laminin, proteoglycans, and elastin. MMP-3 has also been implicated in the degradation of Type III collagen, a key component of dermal and vascular connective tissue.

Experimental studies suggest that Syn-Coll may exert a protective influence on the extracellular matrix by interfering with MMP-mediated collagen degradation. Reports suggest that the peptide may modulate the activity of MMP-1 and MMP-3, thereby reducing enzymatic breakdown of collagen fibrils and contributing to preservation of dermal matrix architecture.^[8]

 

Recent Studies Involving Syn-Coll and Related Peptide Systems

Recent investigations have explored Syn-Coll tripeptide both as a single agent and in combination with other bioactive compounds, often within advanced delivery systems designed to support peptide stability and dermal penetration.

 

Nanoparticle-Based Delivery

A review article^[9] reported on the development of supramolecular collagen nanoparticles incorporating Palmitoyl tripeptide-5 together with lactoferrin and recombinant collagen. Findings from this formulation suggested potential dermal action including improved hydration, increased firmness, and visible reductions in under-eye puffiness and nasolabial fold depth, with reductions of approximately 10% and 22% respectively.

The precise mechanistic contribution of Syn-Coll within the composite system remains unclear, particularly with respect to established pathways involving TGF-β stimulation and matrix metalloproteinase inhibition.

 

Synergistic Peptide Formulations

The same review^[9] highlighted experimental work using nano liposome formulations containing Syn-Coll in combination with other peptides, including Argireline and Carnosine (or similar compounds). These studies assessed anti-aging endpoints such as wrinkle morphology and dermal elasticity. Results suggested that the multi-peptide systems may exert synergistic effects, with reported increased outcomes compared to individual peptide components. Proposed mechanisms for these improvements include potentiation of collagen synthesis, partial inhibition of neurotransmitter release relevant to expression lines, and antioxidant activity. Although promising, the data derive largely from formulation-focused research and require further clarification of Syn-Coll’s distinct mechanistic role within these complexes.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing. Bodily introduction of any sort is strictly prohibited by law. All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

 

References:

1. National Center for Biotechnology Information (2025). PubChem Compound Summary for CID 11950477, Palmitoyl tripeptide-5. https://pubchem.ncbi.nlm.nih.gov/compound/Palmitoyl-tripeptide-5.
2. Murphy-Ullrich, J. E., & Poczatek, M. (2000). Activation of latent TGF-beta by thrombospondin-1: mechanisms and physiology. Cytokine & growth factor reviews, 11(1-2), 59–69. https://doi.org/10.1016/s1359-6101(99)00029-5
3. Gorouhi, F., & Maibach, H. I. (2009). Role of 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
4. Schneider, A. L. (2010). Evaluation of the penetration and efficacy of anti-aging compounds (Doctoral dissertation, Monash University).
5. Kim, H. M., An, H. S., Bae, J. S., Kim, J. Y., Choi, C. H., Kim, J. Y., Lim, J. H., Choi, J. H., Song, H., Moon, S. H., Park, Y. J., Chang, S. J., & Choi, S. Y. (2017). Effects of palmitoyl-KVK-L-ascorbic acid on skin wrinkles and pigmentation. Archives of dermatological research, 309(5), 397–402. https://doi.org/10.1007/s00403-017-1731-6
6. Trookman, N. S., Rizer, R. L., Ford, R., Ho, E., & Gotz, V. (2009). Immediate and Long-term Clinical Benefits of a Treatment for Facial Lines and Wrinkles. The Journal of clinical and aesthetic dermatology, 2(3), 38–43.
7. Varga, J., Rosenbloom, J., & Jimenez, S. A. (1987). Transforming growth factor beta (TGF beta) causes a persistent increase in steady-state amounts of type I and type III collagen and fibronectin mRNAs in normal human dermal fibroblasts. The Biochemical journal, 247(3), 597–604. https://doi.org/10.1042/bj2470597
8. Errante, F., Ledwoń, P., Latajka, R., Rovero, P., & Papini, A. M. (2020). Cosmeceutical Peptides in the Framework of Sustainable Wellness Economy. Frontiers in chemistry, 8, 572923. https://doi.org/10.3389/fchem.2020.572923
9. Badilli U, Inal O. Current Approaches in Cosmeceuticals: Peptides, Biotics and Marine Biopolymers. Polymers (Basel). 2025 Mar 18;17(6):798. doi: 10.3390/polym17060798. PMID: 40292641; PMCID: PMC11946782. https://pmc.ncbi.nlm.nih.gov/articles/PMC11946782/

Decapeptide-12 is a synthetic oligopeptide composed of twelve amino acids (Tyr-Arg-Ser-Aar-Lysd-Tyr-Ser-Ser-Trp-Tyr).^[1] It does not appear to mimic any naturally occurring peptide but was designed by researchers with the intent to target specific enzymatic pathways. The peptide has been primarily studied for its inhibitory potential on tyrosinase, an oxidase enzyme that is considered to play a critical role in melanin biosynthesis.

Chemically, Decapeptide-12 has a molecular formula of C₆₅H₉₀N₁₈O₁₇ and a molecular weight of approximately 1311.46 g/mol. Its structural configuration and sequence are designed to allow interactions with the catalytic domains of tyrosinase, thereby influencing pigment production.

Research interest in Decapeptide-12 extends beyond studies belonging to dermatological and pigmentation contexts. It has also been explored by researchers for its potential role in food preservation, given the apparent involvement of tyrosinase in the oxidation of phenolic compounds in fruits and vegetables. This can lead to discoloration, reduced palatability, and decreased nutritional value. Furthermore, compounds classified as tyrosinase inhibitors, such as Decapeptide-12, have been explored in entomological studies under the hypothesis that the enzyme may be involved in wound healing, immune responses, and cuticle hardening.

 

General Overview of Decapeptide-12

The biological activity of Decapeptide-12 is attributed to its potential capacity to interfere with the catalytic function of tyrosinase. Tyrosinase catalyzes the ortho-hydroxylation of L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), followed by the oxidation of L-DOPA to dopaquinone. These initial reactions constitute the rate-limiting steps of melanogenesis and are deemed indispensable for the subsequent biosynthesis of eumelanin and pheomelanin.

Decapeptide-12 has been reported to inhibit these reactions, potentially by reversibly binding to the active site of tyrosinase and reducing enzymatic turnover of phenolic substrates. This interaction is thought to alter the conformation of the enzyme and limit catalytic efficiency. Additional studies suggest that Decapeptide-12 may influence the transcriptional or translational regulation of the TYR gene, located on chromosome 11, thereby modulating overall tyrosinase expression within melanocytes.

The suggested inhibitory activity of Decapeptide-12 is not restricted to mammalian systems. In plants and food substrates, suppression of tyrosinase-mediated oxidation of phenolic compounds may attenuate enzymatic browning and degradation of organoleptic properties. In insects, where tyrosinase is considered to contribute to wound repair, melanotic encapsulation, and exoskeleton sclerotization, Decapeptide-12 and related inhibitors have been investigated as potential disruptors of developmental and immune pathways.

 

Scientific Research and Studies

 

Decapeptide-12 and Sirtuin Pathway Regulation

Sirtuins constitute a conserved family of NAD⁺-dependent deacetylases that are generally believed to modulate cellular metabolism, genomic stability, and stress responses. Members of this family, particularly SIRT1, have been implicated in glucose and lipid homeostasis, DNA repair, and oxidative stress resistance. Experimental models suggest that sirtuin activation may contribute to delayed cellular senescence and extended lifespan in lower organisms. Compounds such as resveratrol have been suggested to influence sirtuin activity, highlighting the relevance of this pathway in longevity research.

A recent study examined the effect of Decapeptide-12 on sirtuin gene expression in keratinocyte progenitors.^[2] Reverse transcription polymerase chain reaction (RT-PCR) assays were employed to quantify transcriptional responses of seven sirtuin isoforms following 72-hour exposure to varying concentrations of the peptide. The data suggested an apparent upregulation of multiple sirtuin genes with minimal cytotoxicity. Specifically, per the researchers, “Decapeptide-12 [appeared to have] increased transcription of SIRT1 by 141 ± 11% relative to control cells, whereas levels of SIRT3, SIRT6, and SIRT7 were increased by 121 ± 13%, 147 ± 8% and 95± 14%, respectively.”

The observed elevation in SIRT1 expression suggests increased cellular capacity to mitigate oxidative and inflammatory stressors, potentially delaying molecular hallmarks of cell aging and senescence. Increased SIRT3 transcription could imply a role in mitochondrial regulation, energy metabolism, and antioxidant defenses. The strong induction of SIRT6 may be relevant to genomic stability, as this isoform is associated with DNA repair, chromatin regulation, and telomere maintenance. Although the increase in SIRT7 expression appeared modest, it may still reflect modulation of nucleolar activity, ribosomal biogenesis, and cellular stress-sensing. Collectively, these findings suggest that Decapeptide-12 may influence transcriptional regulation of sirtuins, thereby intersecting with pathways linked to cellular longevity and homeostasis.

 

Decapeptide-12 and Pigmentary Dysregulation

Decapeptide-12 has been studied for its potential influence on hyperpigmentation, including melasma, solar lentigines, and other pigmentary irregularities.

A 24-week clinical evaluation^[3] involving 25 models of moderate to severe melasma, periocular lines, and wrinkles suggested apparent improvements across the measured outcomes, with action reported as sustained over the study period.

In a separate 16-week trial, 33 models exhibiting mild-to-moderate melasma were assessed.^[4] The results suggested a visible reduction in the clinical appearance of hyperpigmented lesions. Another study^[5] reported that approximately 25% of the models experienced “complete clearance of melasma after six weeks of [exposure to Decapeptide-12].”

Additional observations highlighted potential in Fitzpatrick phototype IV, a demographic commonly affected by recalcitrant melasma. Across these studies, scientists noted statistically significant improvements in both hyperpigmentation severity and overall aesthetic parameters, suggesting that Decapeptide-12 may modulate pathways associated with melanogenesis and pigmentary homeostasis.

 

Decapeptide-12 and Hyperpigmentation with Inflammation and Photodamage

Decapeptide-12 has been studied for its potential on hyperpigmented lesions arising from both inflammatory events and chronic photodamage.

In research models of Fitzpatrick phototype IV, post-inflammatory hyperpigmentation has been reported to respond to Decapeptide-12 exposure, with observations suggesting an accelerated reduction of hyperpigmented areas relative to placebo. This is hypothesized to involve the peptide’s inhibitory potential on tyrosinase, possibly attenuating melanogenesis in response to inflammatory stimuli.^[6]

Similarly, Decapeptide-12 has been evaluated in the context of solar lentigines, hyperpigmented lesions associated with cumulative ultraviolet exposure. In a 24-week study,^[7] approximately 38.5% of research models exhibited apparent complete clearance of lesions, while all models exhibited some degree of improvement. Subgroup analyses reported improvements from moderate to mild severity in 30.7% of cases, from severe to moderate in 15.4%, and from severe to mild in another 15.4%.

Collectively, these observations suggest that Decapeptide-12 may modulate melanogenic pathways involved in both inflammation-induced and UV-induced hyperpigmentation, supporting its potential role in attenuating pigmentary irregularities across multiple dermatological contexts.

 

Decapeptide-12 on Oxidative Stress

Decapeptide-12 has been studied for its potential to modulate oxidative stress in epidermal keratinocytes. A 2024 study^[8] examined HaCaT cells subjected to hydrogen peroxide (H₂O₂), a widely used model for inducing reactive oxygen species (ROS)-mediated cellular damage. Exposure to Decapeptide-12 was reportedly associated with enhanced cell viability, suggesting a cytoprotective effect under oxidative conditions.

Intracellular ROS levels were apparently markedly reduced following peptide exposure, suggesting a potential attenuation of oxidative stress at the cellular level. Complementary in vitro assays, including ferric reducing antioxidant power (FRAP) and ABTS radical scavenging, further indicated the peptide’s antioxidative potential. These data suggest that Decapeptide-12 may exert a dual function: directly scavenging free radicals and supporting endogenous cellular defenses.

Collectively, these observations suggest that Decapeptide-12 could contribute to the preservation of cellular integrity in the epidermis, potentially mitigating biochemical processes linked to skin aging and photo-induced cellular stress.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing. Bodily introduction of any sort is strictly prohibited by law. All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

 

References:

1. National Center for Biotechnology Information (2025). PubChem Compound Summary for CID 25087629, Decapeptide-12.
2. Basil, M. H., & Anan, A. U. (2019). Tyrosinase inhibitors with potent anti-senescence activity in human neonatal keratinocyte progenitors. J Dermatol Surg Res Ther, 2019, 30-39.
3. Jiang, L., Hino, P. D., Bhatia, A., Stephens, T. J., & Jimenez, F. (2018). Efficacy of Trifecting Night Cream, a Novel Triple acting Skin Brightening Product: A Double-blind, Placebo-controlled Clinical Study. The Journal of clinical and aesthetic dermatology, 11(12), 21–25. https://pmc.ncbi.nlm.nih.gov/articles/PMC6334832/
4. Ramírez, S. P., Carvajal, A. C., Salazar, J. C., Arroyave, G., Flórez, A. M., & Echeverry, H. F. (2013). Open-label evaluation of a novel skin brightening system containing 0.01% decapeptide-12 in combination with 20% buffered glycolic acid for the treatment of mild to moderate facial melasma. Journal of drugs in dermatology : JDD, 12(6), e106–e110. https://pubmed.ncbi.nlm.nih.gov/23839199/
5. Hantash, B. M., & Jimenez, F. (2012). Treatment of mild to moderate facial melasma with the Lumixyl brightening system. Journal of drugs in dermatology : JDD, 11(5), 660–662. https://pubmed.ncbi.nlm.nih.gov/22527440/
6. Chen, J., Bian, J., Hantash, B. M., Albakr, L., Hibbs, D. E., Xiang, X., Xie, P., Wu, C., & Kang, L. (2021). Enhanced skin retention and permeation of a novel peptide via structural modification, chemical enhancement, and microneedles. International journal of pharmaceutics, 606, 120868. https://doi.org/10.1016/j.ijpharm.2021.120868
7. Kassim, A. T., Hussain, M., & Goldberg, D. J. (2012). Open-label evaluation of the skin-brightening efficacy of a skin-brightening system using decapeptide-12. Journal of cosmetic and laser therapy : official publication of the European Society for Laser Dermatology, 14(2), 117–121. https://doi.org/10.3109/14764172.2012.672745
8. Lee SG, Hwang JW, Kang H. Antioxidant and Skin-Whitening Efficacy of a Novel Decapeptide (DP, KGYSSYICDK) Derived from Fish By-Products. Mar Drugs. 2024 Aug 20;22(8):374. doi: 10.3390/md22080374. PMID: 39195491; PMCID: PMC11355700. https://pubmed.ncbi.nlm.nih.gov/39195491/

Syn-AKE is a synthetic tripeptide engineered to possibly replicate the bioactive function of Waglerin-1, a polypeptide component of the venom of the Malaysian Temple Viper (Tropidolaemus wagleri).^[1] Waglerin-1, a 21-amino-acid peptide, appears to exhibit neuromuscular blocking activity by interfering with signal transmission at the neuromuscular junction. Syn-AKE is considered to retain the essential pharmacophore of Waglerin-1 while potentially reducing its length to three amino acids: alanine, proline, and diamino butyrate, chemically formulated as β-alanyl-L-prolyl-3-aminomethyl-L-alanine benzyl amide acetic acid (also known as tripeptide-3).^[2]

The peptide has been investigated primarily in preclinical studies for its potential to modulate neuromuscular activity through interaction with cholinergic receptors. This mechanism is conceptually analogous to that of botulinum neurotoxin, which is widely studied for its inhibitory action on acetylcholine release. Unlike Waglerin-1, which induces paralysis in prey animals, Syn-AKE reportedly represents a simplified synthetic construct designed for controlled biological research into neuromuscular antagonism and muscle relaxation.

 

General Overview of Syn-AKE Tripeptide

Research suggests that Syn-AKE may function as a competitive antagonist at the muscular nicotinic acetylcholine receptor.^[3] Acetylcholine is considered to serve as the primary neurotransmitter responsible for conveying excitatory signals between motor neurons and skeletal muscle fibers. When acetylcholine binds to its receptor, ion channel opening allows for depolarization and subsequent muscle contraction.

By occupying the receptor’s binding site, Syn-AKE is speculated to prevent acetylcholine from interacting with the receptor, thereby potentially inhibiting downstream ion flux and electrical signal propagation. This blockade appears to lead to a reversible suppression of muscle fiber contraction. Studies suggest that this potential may reduce the frequency and intensity of neuromuscular signaling, aligning with the peptide’s design goal of mimicking Waglerin-1’s muscle-relaxing activity in a more targeted and manageable molecular form.

 

Scientific Research and Studies

 

Syn-AKE Tripeptide and Neuromuscular Receptor Interaction

Reports suggest that Waglerin-1, the polypeptide that Syn-AKE mimics, may influence central neurotransmission through interactions with γ-aminobutyric acid (GABA) receptors, an action that could complicate its application in controlled experimental models.

In contrast, preliminary studies^[4] suggest Syn-AKE may not exhibit affinity for GABA receptors, as it was designed instead to selectively interact with nAChRs in peripheral neuromuscular pathways. Structurally, Syn-AKE is a tripeptide that incorporates the minimal sequence elements of Waglerin-1’s active region, thereby potentially conferring receptor-targeting activity without retaining the broader neuropharmacological profile of the parent peptide.

Investigations into Syn-AKE further reports that it m ay reduce responsiveness of muscle-associated nAChRs to acetylcholine, leading to a transient reduction in contraction frequency. For example, one experimental model reported an approximate 80% decrease in the contractile activity of innervated muscle cells within two hours of peptide exposure.^[4]

This possible action may also be reversible, as receptor activity has been reported in some studies to recover following peptide withdrawal. Such findings suggest that the tripeptide may serve as a controlled molecular tool for examining reversible antagonism of cholinergic signaling at the neuromuscular junction.

 

Syn-AKE Tripeptide and Wrinkle Reduction Research

Investigations into Syn-AKE have focused on its potential to attenuate muscle activity and thereby influence the appearance of fine lines and wrinkles. In a controlled three-month trial^[5] involving 37 research models of wrinkling classified as mild-to-moderate, statistically significant improvements were observed in wrinkle parameters shortly after exposure and at subsequent evaluations at one and three months. These findings suggest both immediate and progressive effects over the study period.

Further comparative research^[6] evaluated Syn-AKE alongside other peptides and a placebo in a cohort of 45 models. Results indicated a gradual increase in activity with continued exposure, reaching a reported reduction of up to 52% in wrinkle size on a specified location following four weeks of exposure to a 4% peptide preparation. These studies suggest that repeated exposure may enhance the observed outcomes, with measurable reductions in wrinkle depth and expression line visibility over time.

Preclinical investigations in animal models using topical concentrations between 1% and 4% also reported notable decreases in the appearance of mimic wrinkles. Collectively, these studies highlight the peptide’s potential as a modulator of neuromuscular activity in skin research, though findings remain dependent on experimental context and require cautious interpretation.

 

Syn-AKE Tripeptide and Molecular Anti-Aging Pathways

Beyond its researched potential as a neuromuscular antagonist, Syn-AKE has been evaluated for possible activity in other molecular pathways relevant to cellular aging research.

A 2023 study^[7] employed molecular docking and dynamics simulations to assess the peptide’s interaction with matrix metalloproteinases (MMP-1, -8, and -13) and Sirtuin-1 (SIRT1), proteins implicated in extracellular matrix degradation and cellular aging processes. Results suggested that Syn-AKE exhibited favorable binding stability, particularly with MMP-13 and SIRT1, indicating potential modulatory action on collagen turnover and cellular stress responses.

Complementary in vitro assays provided further insights. Syn-AKE appeared to indicate antioxidant potential in free-radical scavenging assays (DPPH), and apparently exhibited no significant cytotoxic or genotoxic activity in MTT and Ames tests, respectively.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing. Bodily introduction of any sort is strictly prohibited by law. All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

 

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. https://www.researchgate.net/publication/265967863_A_shortened_protecting_group_free_synthesis_of_the_anti-wrinkle_venom_analogue_Syn-Ake_R_exploiting_an_optimized_Hofmann-type_rearrangement
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. Gorouhi, F., & Maibach, H. I. (2009). Role of 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
4. 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
5. 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
6. Pai, V. V., Bhandari, P., & Shukla, P. (2017). Peptides as cosmeceuticals. Indian Journal of Dermatology, Venereology and Leprology, 83, 9. https://pubmed.ncbi.nlm.nih.gov/27451932/
7. Gok B, Budama-Kilinc Y, Kecel-Gunduz S. Anti-aging activity of Syn-AKE Tripeptide by in silico approaches and in vitro tests. J Biomol Struct Dyn. 2024 Jul;42(10):5015-5029. doi: 10.1080/07391102.2023.2223681. Epub 2023 Jun 22. PMID: 37349941. https://pubmed.ncbi.nlm.nih.gov/37349941/

Selank is a synthetic heptapeptide structurally derived from the endogenously occurring tetrapeptide Tuftsin.^[1] The peptide sequence comprises the Tuftsin fragment at the N-terminus and a tripeptide Pro-Gly-Pro (PGP) motif at the C-terminal end. The incorporation of the PGP sequence is suggested to influence the peptide’s physiochemical potential in supporting interaction with lipid-rich biological membranes.

Selank was initially developed in Russia as a synthetic analogue of Tuftsin, designed to improve metabolic stability and prolong half-life relative to the native peptide. Research suggests that Selank might exert modulatory effects on immunological processes, with potential interactions involving T helper cells and interleukin-6 (IL-6) signaling pathways.

The mechanism of action of Selank is hypothesized to involve several interconnected pathways. The peptide may influence monoamine neurotransmitter systems and contribute to the regulation of brain-derived neurotrophic factor (BDNF), suggesting a role in neurotrophic and neuro-regulatory functions. The PGP motif within Selank is thought to facilitate peptide transit across the blood-brain barrier (BBB) by potentially interacting with transport systems or receptors, thereby enabling receptor-mediated endocytosis or active transport. Structural modifications in the tertiary conformation of Selank may further enhance compatibility with the BBB, potentially allowing it to engage central nervous system targets. Additionally, the immunomodulatory properties of Selank, inferred from its Tuftsin component, might influence phagocytic activity, cell motility, and other aspects of immune cell function.^[2]

 

Scientific Research and Studies

 

GABAergic Modulation

Selank has been proposed to influence gamma-aminobutyric acid (GABA) neurotransmission, a system recognized for its inhibitory role in neuronal excitability. Experimental studies in rodent models suggest that Selank may induce transcriptional changes in genes associated with GABA signaling. In one study,^[3] the expression of 84 genes linked to neurotransmission was examined following exposure to Selank or GABA. The results indicated a positive correlation between gene expression patterns, implying that Selank might modulate the GABAergic system indirectly through transcriptional regulation rather than direct receptor activation alone.

Distinct variations in specific gene expression compared to GABA further suggest potential allosteric or modulatory mechanisms. Such action may contribute to persistent alterations in neurotransmitter dynamics, providing a mechanistic basis for the peptide’s sustained anxiolytic potential observed in experimental settings.

Additional studies appear to suggest that Selank may alter the functional properties of GABA receptors, potentially modifying receptor affinity for GABA and supporting inhibitory signaling. This modulatory action appears to be synergistic with classical allosteric modulators of GABA receptors, such as benzodiazepines, although Selank may lack the dependence and amnestic effects typically associated with these agents.

Based on preclinical study reports, it is suggested that Selank might influence enzymatic pathways involved in encephalin degradation, which could indirectly affect GABAergic tone by preserving endogenous anxiolytic peptides. Collectively, these observations highlight a multifaceted mechanism whereby Selank could hypothetically affect both gene expression and receptor-mediated neurotransmission, supporting a complex role in neuro-regulation and potential anxiolytic activity.

 

BDNF Modulation

Per the preclinical reports, it appears that Selank may affect the expression of brain-derived neurotrophic factor (BDNF), a protein implicated in neuronal survival, growth, and synaptic plasticity.

Experimental data^[3] from rodent models suggest that Selank could increase BDNF mRNA levels in the hippocampus, a region associated with memory processing and emotional regulation. This potential upregulation of BDNF appears particularly relevant under conditions where stress or elevated glucocorticoids are considered to suppress BDNF expression. Such actions imply a possible role for Selank in supporting neuroplasticity and adaptive synaptic function, although the precise molecular mechanisms remain to be elucidated.

 

Selank Heptapeptide and Serotonergic Activity

Data from murine model studies suggests that Selank may interact with serotonergic pathways, which are widely implicated in mood and anxiety regulation. In models where serotonin synthesis was experimentally reduced, Selank exposure appeared to modulate serotonin metabolism, particularly in brainstem regions involved in neurotransmitter regulation. These findings propose that Selank might facilitate the metabolic processing of serotonin, potentially counteracting diminished serotonergic activity. The modulation of serotonin metabolism by Selank may represent one of several mechanisms through which it influences neural systems associated with emotional and cognitive responses.

 

Selank Heptapeptide and Cognitive Function

Preclinical investigations^[3] suggest that Selank may influence learning and memory processes. In murine models trained in a conditioned avoidance response (CAR) paradigm over four consecutive days, exposure to Selank prior to training appeared to correlate with improved performance, based on the reported reduction in errors and an increase in correct responses by the experiment models. Researchers state that the:

“results [indicated] that Selank caused a number of alterations in the expression of genes involved in neurotransmission. The data obtained indicate that Selank is characterized by its complex effects on nerve cells, and one of its possible molecular mechanisms is associated with allosteric modulation of the GABAergic system.”

Selank may also potentially modulate neural circuits associated with memory consolidation, by enhancing synaptic stability and efficiency. By mitigating factors related to anxiety, which may interfere with cognitive performance, the peptide might further support learning outcomes. Additionally, Selank may promote neural plasticity, particularly within cognitive circuits exhibiting suboptimal activity, suggesting a potential to facilitate adaptive changes in neuronal function. These findings pose that Selank may exert multifaceted influence on cognitive regulation, warranting further investigation into its potential impact on neurocognitive pathways.

 

Selank Heptapeptide and Gene Expression

Preclinical research has investigated the possible influence of Selank on genome expression and its potential involvement in inflammatory regulation. In one study,^[4] male murine models were assigned to three groups: control, single exposure to Selank, and repeated Selank exposure. RNA isolated from the spleen and hippocampus was analyzed via PCR. Based on the findings, it was reported that Selank may have modulated gene expression, with pronounced effects observed in both the spleen and hippocampus. Notably, alterations in CX3CR1 expression, a gene implicated in inflammatory pathways, suggest that Selank might influence inflammatory signaling through transcriptional regulation. These observations point to a possible immunomodulatory mechanism mediated at the genomic level.

 

Encephalin Pathways

Investigations^[5] have also explored Selank’s interaction with enkephalin signaling. In experimental models of generalized anxiety disorder, Selank introduction appeared to modulate levels of tau-leu-enkephalins, endogenous opioid peptides involved in mood, stress, and nociceptive regulation. The peptide is hypothesized to suppress enzymatic degradation of enkephalins, thereby potentially supporting their physiological activity. Preclinical findings suggested that such inhibition could elevate enkephalin half-life and availability, suggesting a mechanism by which Selank may contribute to anxiolytic and neuroregulatory effects. Comparisons with classical benzodiazepine compounds suggest that Selank’s influence on enkephalin pathways may represent a complementary or alternative route for modulating stress-related biochemical systems.

 

Selank Heptapeptide and Immune Regulation

Preclinical studies have explored the potential immune-regulatory properties of Selank. In experimental models^[6] of generalized anxiety disorder (GAD) with features of neurasthenia, models were exposed to Selank over a 14-day period. Peripheral blood analysis revealed transient elevations in interleukin-6 (IL-6) concentrations, accompanied by shifts in the Th1/Th2 cytokine ratio. These observations suggest that Selank may influence the balance of pro- and anti-inflammatory signaling pathways, highlighting a potential role in modulating immune responses. The findings point toward a complex interaction between Selank and immune regulatory networks, although the precise cellular mechanisms remain to be fully elucidated.

 

Selank Heptapeptide and Cardiovascular Dynamics

The potential link between Selank and cardiovascular processes have been evaluated in feline models. Following peptide exposure,^[7] arterial blood pressure appeared to exhibit a rapid reduction of over 30% within the first three minutes. Cerebral blood flow reportedly increased by over 20% during the initial 10 minutes, gradually stabilizing to baseline levels. Notably, no significant alterations in heart rate or respiratory parameters were observed. These findings imply that Selank may selectively influence vascular tone and cerebral perfusion without eliciting generalized cardiovascular or respiratory action, suggesting targeted hemodynamic modulation.

 

Selank Heptapeptide and Withdrawal-Related Responses

Experimental investigations^[8] have examined the potential of Selank to influence withdrawal phenomena. In rodent models subjected to chronic ethanol exposure followed by abrupt cessation, exposure to Selank appeared to be “[possibly] effective in eliminating of alcohol withdrawal symptoms,” as per the researchers. Measures of social interaction and performance in maze-based tasks suggested a reduction in withdrawal-associated anxiety and cognitive disruption. These results suggest that Selank may influence neural circuits implicated in stress and reward processing, potentially attenuating withdrawal-related behavioral changes through neuro-modulatory pathways.

 

Selank Heptapeptide and Lipid Metabolism

Research studies^[9] examined the potential interaction of Selank on lipid profiles and weight regulation in murine models subjected to a high-fat diet for six weeks. Following diet induction, subjects were divided into an experimental group receiving Selank, a control group introduced to sodium chloride, and an unexposed baseline group monitored for comparison. Based on the analysis, it can be said that Selank exposure was associated with reductions in total cholesterol, low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), triglycerides, and overall fat content, with observed decreases ranging from approximately 25% to over 50%.

Additional findings suggest that Selank may influence lipid and glucose metabolism, as suggested by improvements in hemostatic parameters, including increased total fibrinolytic activity and reduced platelet aggregation. These changes point to potential modulation of clot formation processes. Furthermore, measurements of glucose homeostasis suggested stabilization of blood glucose levels, while fat metabolism rates in the Selank group approached levels observed in baseline control models. Body weight analysis revealed that the experimental group maintained or gradually reduced weight during peptide exposure, whereas the control group experienced an average weight gain of 40g over the study period. Collectively, these observations suggest that Selank may exert multifactorial effects on lipid regulation, hemostasis, and metabolic stability.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing. Bodily introduction of any sort is strictly prohibited by law. All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

 

References:

1. Kozlovskaya MM, Kozlovskii II, Val’dman EA, Seredenin SB. Selank and short peptides of the tuftsin family in the regulation of adaptive behavior in stress. Neurosci Behav Physiol. 2003 Nov;33(9):853-60. https://pubmed.ncbi.nlm.nih.gov/14969422/
2. Elena Filatova et al., GABA, Selank, and Olanzapine Affect the Expression of Genes Involved in GABAergic Neurotransmission in IMR-32 Cells. https://doi.org/10.3389/fphar.2017.00089
3. Volkova, A., Shadrina, M., Kolomin, T., Andreeva, L., Limborska, S., Myasoedov, N., & Slominsky, P. (2016). Selank Administration Affects the Expression of Some Genes Involved in GABAergic Neurotransmission. Frontiers in pharmacology, 7, 31. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757669/
4. T. T.A Kolomin et al., Transcriptomic Response of Rat Hippocampus and Spleen Cells to Single and Chronic Administration of the Peptide Selank. June 2, 2009. DOI: 10.1134/S1607672910010023
5. Zozulia AA, Neznamov GG, Siuniakov TS, Kost NV, Gabaeva MV, Sokolov OIu, Serebriakova EV, Siranchieva OA, Andriushenko AV, Telesheva ES, Siuniakov SA, Smulevich AB, Miasoedov NF, Seredenin SB. Efficacy and possible mechanisms of action of a new peptide anxiolytic selank in the therapy of generalized anxiety disorders and neurasthenia. Zh Nevrol Psikhiatr Im S S Korsakova. 2008;108(4):38-48. Russian. https://pubmed.ncbi.nlm.nih.gov/18454096/
6. Uchakina ON, Uchakin PN, Miasoedov NF, Andreeva LA, Shcherbenko VE, Mezentseva MV, Gabaeva MV, Sokolov OIu, Zozulia AA, Ershov FI. Immunomodulatory effects of selank in patients with anxiety-asthenic disorders. Zh Nevrol Psikhiatr Im S S Korsakova. 2008;108(5):71-5. Russian. https://pubmed.ncbi.nlm.nih.gov/18577961/
7. Gan’shina TS, Kozlovskiĭ II. [Effects of the new peptide anxiolytic drug selank on the cardiovascular system functioning and respiration in cats]. Eksp Klin Farmakol. 2005 Jul-Aug;68(4):33-5. Russian. https://pubmed.ncbi.nlm.nih.gov/16193654/
8. Kolik LG, Nadorova AV, Kozlovskaya MM. Efficacy of peptide anxiolytic selank during modeling of withdrawal syndrome in rats with stable alcoholic motivation. Bull Exp Biol Med. 2014 May;157(1):52-5. https://pubmed.ncbi.nlm.nih.gov/24913576/
9. N.F. Mjasoedov et al, The Influence of Selank on the Parameters of the Hemostasis System, Lipid Profile, and Blood Sugar Level in the Course of Experimental Metabolic Syndrome. April 14, 2014. https://pubmed.ncbi.nlm.nih.gov/25371249/