@article{3333,
  keywords = {Humans, Signal Transduction, Oligopeptides, Female, Male, Cells, Cultured, Adult, Cysteine, Keratinocytes, Inflammation, Young Adult, Diglycerides, Peptidoglycan, Adolescent, Lipopeptides, Acne Vulgaris, Benzoyl Peroxide, Dermatologic Agents, Interleukin-1alpha, Interleukin-8, Proline, Propionibacterium acnes, Severity of Illness Index, Single-Blind Method, Toll-Like Receptor 2},
  author = {Jos{\'e} Fern{\'a}ndez and Corey Webb and Karl Rouzard and Jason Healy and Masanori Tamura and Michael Voronkov and Kristen Huber and Jeffry Stock and Maxwell Stock and Joel Gordon and Edwardo P{\'e}rez},
  title = {SIG1459: A novel phytyl-cysteine derived TLR2 modulator with in vitro and clinical anti-acne activity.},
  abstract = { <p>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{\textquoteright}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.</p> },
  year = {2018},
  journal = {Exp Dermatol},
  volume = {27},
  pages = {993-999},
  month = {2018 Sep},
  issn = {1600-0625},
  doi = {10.1111/exd.13692},
  language = {eng},
}