title: Lipolanthionine peptides act as inhibitors of TLR2-mediated IL-8 secretion. Synthesis and structure-activity relationships.
abstract: Lipoproteins from gram-positive and -negative bacteria, mycoplasma, and shorter synthetic lipopeptide analogues activate cells of the innate immune system via the Toll-like receptor TLR2/TLR1 or TLR2/TLR6 heterodimers. For this reason, these compounds constitute highly active adjuvants for vaccines either admixed or covalently linked. The lanthionine scaffold has structural similarity with the S-(2,3-dihydroxypropyl)cysteine core structure of the lipopeptides. Therefore, lanthionine-based lipopeptide amides were synthesized and probed for activity as potential TLR2 agonists or antagonists. A collection of analytically defined lipolanthionine peptide amides exhibited an inhibitory effect of the TLR2-mediated IL-8 secretion when applied in high molar excess to the agonistic synthetic lipopeptide Pam3Cys-Ser-(Lys)4-OH. Structure-activity relationships revealed the influence of the chirality of the two alpha-carbon atoms, the chain lengths of the attached fatty acids and fatty amines, and the oxidation level of the sulfur atom on the inhibitory activity of the lipolanthionine peptide amides.
authors.affiliation: Institute of Organic Chemistry, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Seyberth
authors.forename: Söhnke
authors.initials: S
authors.lastname: Voss
authors.forename: Roland
authors.initials: R
authors.lastname: Brock
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Wiesmüller
authors.forename: Günther
authors.initials: G
authors.lastname: Jung
mesh_terms: D000276:Adjuvants, Immunologic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D005227:Fatty Acids / Q000737:chemistry*; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors*
chemical_list: D000276:Adjuvants, Immunologic; D005227:Fatty Acids; D016209:Interleukin-8; D009842:Oligopeptides; D013440:Sulfides; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; C001520:lanthionine; D000409:Alanine