Abstract
Over the past 15 years, small molecule isoprenylcysteine (IPC) analogs have been identified as a potential new class of topical anti-inflammatories. Clinical studies have demonstrated that IPCs are both safe and effective in promoting healthy skin when applied topically. This work aims to demonstrate N-Succinyl-S-farnesyl-L-cysteine (SFC) as a novel IPC molecule that provides a broad spectrum of benefits for skin. Human promyelocytic cell line HL-60, human dermal microvascular endothelial cells (HDMECs), human dermal fibroblasts (HDFs), and normal human epidermal keratinocytes (NHEKs) were exposed in culture to various inducers to trigger reactive oxygen species, cytokines, or collagenase production. A 49-subject randomized double-blind, vehicle-controlled, split face trial was performed with 1% SFC gel, or 5% niacinamide and vehicle applied for 12 weeks to evaluate anti-wrinkle and anti-aging endpoints. We demonstrated that SFC inhibited GPCR and TLR-induced pro-inflammatory cytokine release in NHEKs and HDMECs from several inflammatory inducers such as UVB, chemicals, cathelicidin, and bacteria. SFC successfully reduced GPCR-induced oxidation in differentiated neutrophils. Moreover, photoaging studies showed that SFC reduced UVA-induced collagenase (pro-MMP-1) production in HDFs. Clinical assessment of 1% SFC gel demonstrated improvement above the vehicle for wrinkle reduction, hydration, texture, and overall appearance of skin. N-Succinyl-S-farnesyl-L-cysteine (SFC) is a novel anti-inflammatory small molecule and is the first farnesyl-cysteine IPC shown to clinically improve appearance and signs of aging, while also having the potential to ameliorate inflammatory skin disorders.
Highlights
Introduction published maps and institutional affilSmall molecule isoprenylcysteine (IPC) analogs have been identified as a potential novel class of topical anti-inflammatories
Proteins, which is essential to membrane targeting of heterotrimeric and small G-proteins that mediate receptor signaling in eukaryotic cells
Our results show that SFC dose-dependently re6 of 11 compaduces PGN-induced interleukin-8 (IL-8) release in normal human epidermal keratinocytes (NHEKs) with an IC50 = 0.8 μM, rable to clobetasol with an IC50 = 1 μM (Figure 2B)
Summary
Introduction published maps and institutional affilSmall molecule isoprenylcysteine (IPC) analogs have been identified as a potential novel class of topical anti-inflammatories. IPC analogs contain a 15- or 20-carbon side chain attached to the amino acid cysteine, mimicking the C-terminus of processed CAAX proteins, which is essential to membrane targeting of heterotrimeric and small G-proteins that mediate receptor signaling in eukaryotic cells. IPC analogs inhibit signaling activation at the membrane compartment by competing with isoprenoid groups for prenyl-binding sites [1,2] and by disrupting signal transduction by preventing heterotrimeric G-protein formation and/or presumably by blocking downstream G-protein-effector interactions [3,4,5]. Since the initial discovery of N-Acetyl-S-farnesyl-L-cysteine (AFC) as the first IPC analog to effectively downregulate inflammatory responses in platelets, macrophages, and neutrophils [6,7,8], several different IPC analogs have been discovered and reported to provide a variety of different activities in skin, including inhibiting G-protein coupled receptor iations.
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