Anti‐inflammatory and anti‐bacterial properties of tetramethylhexadecenyl succinyl cysteine (<scp>TSC</scp>): a skin‐protecting cosmetic functional ingredient

Fernández, José R.; Rouzard, Karl; Voronkov, Michael V.; Huber, Kristen L.; Stock, Jeffry B.; Stock, Maxwell; Gordon, Joel S.; Pérez, Eduardo Salcedo

doi:10.1111/ics.12166

Cited by 8 publications

(14 citation statements)

References 26 publications

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“…1a) in which a glutamine is thioacetylated to the cysteine residue possesses anti-inflammatory properties by inhibiting UV-induced pro-inflammatory mediators in human keratinocytes, similar to previous IPC compounds [15, 16]. Furthermore, we demonstrate for the first time that SIG-1191 upregulates AQP3 gene expression in monolayer keratinocytes and both gene expression and protein production in reconstructed three-dimensional human skin cultured at the air–liquid interface.…”

Section: Introductionsupporting

confidence: 80%

N-Acetylglutaminoyl-S-farnesyl-l-cysteine (SIG-1191): an anti-inflammatory molecule that increases the expression of the aquaglyceroporin, aquaporin-3, in human keratinocytes

et al. 2016

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Isoprenylcysteine (IPC) small molecules were discovered as signal transduction modulating compounds ~25 years ago. More recently, IPC molecules have demonstrated antioxidant and anti-inflammatory properties in a variety of dermal cells as well as antimicrobial activity, representing a novel class of compounds to ameliorate skin conditions and disease. Here, we demonstrate a new IPC compound, N-acetylglutaminoyl-S-farnesyl-l-cysteine (SIG-1191), which inhibits UVB-induced inflammation blocking pro-inflammatory cytokine interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) production. To investigate further the previously reported hydrating potential of IPC compounds, SIG-1191 was tested for its ability to modulate aquaporin expression. Specifically, aquaporin 3 (AQP3) the most abundant aquaporin found in skin has been reported to play a key role in skin hydration, elasticity and barrier repair. Results show here for the first time that SIG-1191 increases AQP3 expression in both cultured normal human epidermal keratinocytes as well as when applied topically in a three-dimensional (3D) reconstructed human skin equivalent. Additionally, SIG-1191 dose dependently increased AQP3 protein levels, as determined by specific antibody staining, in the epidermis of the 3D skin equivalents. To begin to elucidate which signaling pathways SIG-1191 may be modulating to increase AQP3 levels, we used several pharmacological pathway inhibitors and determined that AQP3 expression is mediated by the Mitogen-activated protein kinase/Extracellular signal-regulated kinase kinase (MEK) pathway. Altogether, these data suggest SIG-1191 represents a new IPC derivative with anti-inflammatory activity that may also promote increased skin hydration based on its ability to increase AQP3 levels.

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Section: Introductionsupporting

confidence: 80%

N-Acetylglutaminoyl-S-farnesyl-l-cysteine (SIG-1191): an anti-inflammatory molecule that increases the expression of the aquaglyceroporin, aquaporin-3, in human keratinocytes

et al. 2016

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“…Isoprenylcysteine (IPC) small molecules have been identified as a novel class of topical anti‐inflammatory and antimicrobial cosmetic functional ingredients (CFI) . IPCs have been shown to inhibit signaling activation in the membrane, by competing with isoprenoid groups for prenyl‐binding sites on membrane‐associated proteins .…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…SIG1273 (tetramethylhexadecenyl succinyl cysteine) is a second generation IPC CFI with anti‐inflammatory activity and was the first reported IPC to also have antimicrobial properties . SIG1273 has a broad range of anti‐inflammatory activities, abrogating toll‐like receptor 2 (TLR2), toll‐like receptor 4 (TLR4), and T‐cell receptor (TCR) signaling . Moreover, SIG1273 was shown to inhibit ultraviolet B (UVB), phorbol 12‐myristate 13‐acetate (TPA) and Propionibacterium acnes induced pro‐inflammatory cytokine release and in a clinical study was shown to provide a benefit to individuals with acne prone skin by reducing P. acnes counts and reducing inflammation …”

Section: Introductionmentioning

confidence: 99%

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In vitro and clinical evaluation of SIG1273: a cosmetic functional ingredient with a broad spectrum of anti‐aging and antioxidant activities

Fernández

Rouzard

Voronkov

et al. 2016

J of Cosmetic Dermatology

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SummaryBackground Isoprenylcysteine (IPC) small molecules were identified as a new class of anti-inflammatory compounds over 20 years ago. Since then, they have been developed as novel cosmetic functional ingredients (CFI) and topical drug candidates. SIG1273 is a second generation CFI that has previously been shown to provide a broad spectrum of benefits for the skin through its anti-inflammatory and antimicrobial properties. Objective To determine whether SIG1273 possesses anti-aging properties in vitro and evaluate the tolerability and activity of SIG1273 when applied topically to human subjects. Methods To model photoaging in vitro, human dermal fibroblasts (HDFs) were exposed in culture to UVA to induce collagenase (MMP-1) production. An in vitro woundhealing model was based on the activation of HDF migration into cell-free tissue culture surface. Hydrogen peroxide-induced oxidative stress was performed using HDFs to measure intracellular ROS activity. Radical scavenging capacity was determined using a colorimetric antioxidant assay kit (ABTS method). Lastly, a 4-week, 29-subject study was performed in which SIG1273 was applied topically as a cream to assess its tolerance and activity in reducing the appearance of aging.Results In vitro studies demonstrate SIG1273 inhibits UVA-induced MMP-1 production, hydrogen peroxide-induced oxidative stress and promotes wound healing. Moreover, SIG1273 was shown to be a radical scavenging antioxidant. Clinical assessment of SIG1273 cream (0.25%) showed it was well tolerated with significant improvement in the appearance of fine lines, coarse wrinkles, radiance/luminosity, pore size, texture/smoothness, hydration and increased firmness. Conclusions SIG1273 represents a novel CFI with antioxidant, anti-aging, and antiinflammatory properties that when applied topically is well tolerated and provides benefits to individuals with aging skin.

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“…Previously, we reported that IPC compounds inhibited TLR2‐ and TLR4‐induced pro‐inflammatory cytokine production of IL‐6 and IL‐8 and possessed antibacterial activity . As demonstrated here, subsequent medicinal chemistry efforts yielded a novel phytyl IPC, SIG1459 (Tetramethyl‐hexadecenyl‐cysteine‐formylprolinate) with antibacterial activity against the gram‐positive organism, including eradicating biofilm formation and inhibiting TLR2‐induced inflammation (Table and ).…”

Section: Discussionmentioning

confidence: 56%

SIG1459: A novel phytyl‐cysteine derived TLR2 modulator with in vitro and clinical anti‐acne activity

Fernández

Webb

Rouzard

et al. 2018

Experimental Dermatology

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Cutibacterium (formerly Propionibacterium acnes) is a major contributor to the pathogenesis of acne. C. acnes initiates an innate immune response in keratinocytes via recognition and activation of toll-like receptor-2 (TLR2), a key step in comedogenesis. Tetramethyl-hexadecenyl-cysteine-formylprolinate (SIG1459), a novel anti-acne isoprenylcysteine (IPC) small molecule, is shown in this study to have direct antibacterial activity and inhibit TLR2 inflammatory signalling. In vitro antibacterial activity of SIG1459 against C. acnes was established demonstrating minimal inhibitory concentration (MIC = 8.5 μmol\L), minimal bactericidal concentration (MBC = 16.1 μmol\L) and minimal biofilm eradication concentration (MBEC = 12.5 μmol\L). To assess SIG1459's anti-inflammatory activity, human keratinocytes were exposed to C. acnes and different TLR2 ligands (peptidoglycan, FSL-1, Pam3CSK4) that induce pro-inflammatory cytokine IL-8 and IL-1α production. Results demonstrate SIG1459 inhibits TLR2-induced IL-8 release from TLR2/TLR2 (IC = 0.086 μmol\L), TLR2/6 (IC = 0.209 μmol\L) and IL-1α from TLR2/TLR2 (IC = 0.050 μmol\L). To assess the safety and in vivo anti-acne activity of SIG1459, a vehicle controlled clinical study was conducted applying 1% SIG1459 topically (n = 35 subjects) in a head-to-head comparison against 3% BPO (n = 15 subjects). Utilizing the Investigator Global Assessment scale for acne as primary endpoint, results demonstrate 1% SIG1459 significantly outperformed 3% BPO over 8 weeks, resulting in 79% improvement as compared to 56% for BPO. Additionally, 1% SIG1459 was well tolerated. Thus, SIG1459 and phytyl IPC compounds represent a novel anti-acne technology that provides a safe dual modulating benefit by killing C. acnes and reducing the inflammation it triggers via TLR2 signalling.

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Anti‐inflammatory and anti‐bacterial properties of tetramethylhexadecenyl succinyl cysteine (TSC): a skin‐protecting cosmetic functional ingredient

Abstract: Tetramethylhexadecenyl succinyl cysteine represents a novel cosmetic functional ingredient that provides a dual modulating benefit of skin protection to individuals by reducing inflammation in keratinocytes, endothelial and mononuclear cell types and S. pyogenes counts.

Cited by 8 publications

References 26 publications

N-Acetylglutaminoyl-S-farnesyl-l-cysteine (SIG-1191): an anti-inflammatory molecule that increases the expression of the aquaglyceroporin, aquaporin-3, in human keratinocytes

N-Acetylglutaminoyl-S-farnesyl-l-cysteine (SIG-1191): an anti-inflammatory molecule that increases the expression of the aquaglyceroporin, aquaporin-3, in human keratinocytes

In vitro and clinical evaluation of SIG1273: a cosmetic functional ingredient with a broad spectrum of anti‐aging and antioxidant activities

SIG1459: A novel phytyl‐cysteine derived TLR2 modulator with in vitro and clinical anti‐acne activity

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