title: Structure-activity relationships in human Toll-like receptor 2-specific monoacyl lipopeptides.
abstract: Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM(2)CS) compounds are potential vaccine adjuvants. We had previously determined that at least one acyl group of optimal length (C(16)) and an appropriately orientated ester carbonyl group is essential for TLR2-agonistic activity. We now show that these structurally simpler analogues display agonistic activities with human, but not murine, TLR2. SAR studies on the monoacyl derivatives show that the optimal acyl chain length is C(16), and aryl substituents are not tolerated. A variety of alkyl and acyl substituents on the cysteine amine were examined. All N-alkyl derivatives were inactive. In contradistinction, short-chain N-acyl analogues were found to be highly active, with a clear dependence on the chain length. A cysteine N-acetyl analogue was found to be the most potent (EC(50): 1 nM), followed by the N-butyryl analogue. The N-acetyl analogue is human TLR2-specific, with its potency comparable to that of PAM(2)CS.
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, Multidisciplinary Research Building, Room 320D, 2030 Becker Drive, Lawrence Kansas 66047, USA.
authors.forename: Deepak B
authors.initials: DB
authors.lastname: Salunke
authors.forename: Nikunj M
authors.initials: NM
authors.lastname: Shukla
authors.forename: Euna
authors.initials: E
authors.lastname: Yoo
authors.forename: Breanna M
authors.initials: BM
authors.lastname: Crall
authors.forename: Rajalakshmi
authors.initials: R
authors.lastname: Balakrishna
authors.forename: Subbalakshmi S
authors.initials: SS
authors.lastname: Malladi
authors.forename: Sunil A
authors.initials: SA
authors.lastname: David
mesh_terms: D000276:Adjuvants, Immunologic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D004151:Dipeptides / Q000494:pharmacology; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D055666:Lipopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008074:Lipoproteins / Q000494:pharmacology; D051379:Mice; D016328:NF-kappa B / Q000096:biosynthesis; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000235:genetics
chemical_list: D000276:Adjuvants, Immunologic; D004151:Dipeptides; D055666:Lipopeptides; D008074:Lipoproteins; D016328:NF-kappa B; D051195:Toll-Like Receptor 2; C047210:2,3-bis-(palmitoyloxy)-2-propyl-N-palmitoyl-cysteinylserine