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

Publisher: Munksgaard Country of Publication: Denmark NLM ID: 9301549 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1600-0625 (Electronic) Linking ISSN: 09066705 NLM ISO Abbreviation: Exp Dermatol Subsets: MEDLINE

Original Publication: Copenhagen : Munksgaard, c1992-

Acne Vulgaris/*drug therapy ; Cysteine/*analogs & derivatives ; Dermatologic Agents/*therapeutic use ; Inflammation/*metabolism ; Keratinocytes/*metabolism ; Proline/*analogs & derivatives ; Signal Transduction/*drug effects ; Toll-Like Receptor 2/*antagonists & inhibitors; Adolescent ; Adult ; Benzoyl Peroxide/therapeutic use ; Cells, Cultured ; Cysteine/pharmacology ; Cysteine/therapeutic use ; Dermatologic Agents/pharmacology ; Diglycerides/pharmacology ; Female ; Humans ; Interleukin-1alpha/metabolism ; Interleukin-8/metabolism ; Keratinocytes/drug effects ; Lipopeptides/pharmacology ; Male ; Oligopeptides/pharmacology ; Peptidoglycan/pharmacology ; Proline/pharmacology ; Proline/therapeutic use ; Propionibacterium acnes/drug effects ; Severity of Illness Index ; Single-Blind Method ; Young Adult

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 50  = 0.086 μmol\L), TLR2/6 (IC 50  = 0.209 μmol\L) and IL-1α from TLR2/TLR2 (IC 50  = 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.
(© 2018 The Authors. Experimental Dermatology Published by John Wiley & Sons Ltd.)

Keywords: Cutibacterium acnes; acne; anti-inflammatory; isoprenylcysteine analog; toll-like receptor

0 (CXCL8 protein, human)
0 (Dermatologic Agents)
0 (Diglycerides)
0 (FSL-1 lipoprotein, synthetic)
0 (IL1A protein, human)
0 (Interleukin-1alpha)
0 (Interleukin-8)
0 (Lipopeptides)
0 (Oligopeptides)
0 (Pam(3)CSK(4) peptide)
0 (Peptidoglycan)
0 (SIG1459)
0 (TLR2 protein, human)
0 (Toll-Like Receptor 2)
9DLQ4CIU6V (Proline)
K848JZ4886 (Cysteine)
W9WZN9A0GM (Benzoyl Peroxide)

Date Created: 20180526 Date Completed: 20190624 Latest Revision: 20190816

20231215

10.1111/exd.13692

29797368