title: N-Acetylglutaminoyl-S-farnesyl-L-cysteine (SIG-1191): an anti-inflammatory molecule that increases the expression of the aquaglyceroporin, aquaporin-3, in human keratinocytes.
abstract: 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.
authors.affiliation: Signum Dermalogix, 133 Wall Street, Princeton, NJ, 08540, USA.
authors.forename: José R
authors.initials: JR
authors.lastname: Fernández
authors.affiliation: Signum Dermalogix, 133 Wall Street, Princeton, NJ, 08540, USA.
authors.forename: Corey
authors.initials: C
authors.lastname: Webb
authors.affiliation: Signum Dermalogix, 133 Wall Street, Princeton, NJ, 08540, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Rouzard
authors.affiliation: Signum Dermalogix, 133 Wall Street, Princeton, NJ, 08540, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Voronkov
authors.affiliation: Signum Dermalogix, 133 Wall Street, Princeton, NJ, 08540, USA.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Huber
authors.affiliation: Signum Dermalogix, 133 Wall Street, Princeton, NJ, 08540, USA.|Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
authors.forename: Jeffry B
authors.initials: JB
authors.lastname: Stock
authors.affiliation: Signum Dermalogix, 133 Wall Street, Princeton, NJ, 08540, USA.
authors.forename: Maxwell
authors.initials: M
authors.lastname: Stock
authors.affiliation: Signum Dermalogix, 133 Wall Street, Princeton, NJ, 08540, USA.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Gordon
authors.affiliation: Signum Dermalogix, 133 Wall Street, Princeton, NJ, 08540, USA. eperez@signumbio.com.
authors.forename: Eduardo
authors.identifier: http://orcid.org/0000-0002-7112-6896
authors.initials: E
authors.lastname: Perez
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D051400:Aquaporin 3 / Q000096:biosynthesis / Q000378:metabolism*; D004151:Dipeptides / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D055103:Hypodermoclysis / Q000379:methods; D007249:Inflammation / Q000188:drug therapy; D015850:Interleukin-6 / Q000096:biosynthesis*; D015603:Keratinocytes / Q000378:metabolism*; D055666:Lipopeptides / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000166:cytology / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D000893:Anti-Inflammatory Agents; D004151:Dipeptides; C508600:IL6 protein, human; D015850:Interleukin-6; D055666:Lipopeptides; C000615782:N-acetylglutaminoyl-S-farnesylcysteine; D014409:Tumor Necrosis Factor-alpha; D051400:Aquaporin 3; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Aquaglyceroporin-3; Inflammation; Isoprenylcysteine; Skin hydration