title: Structure-activity relationships in toll-like receptor 2-agonists leading to simplified 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. In continuation of previously reported structure-activity relationships on this chemotype, we have determined that at least one acyl group of optimal length (C(16)) and an appropriately oriented ester carbonyl group is essential for TLR2-agonistic activity. The spacing between one of the palmitoyl ester carbonyl and the thioether is crucial to allow for an important H-bond, which observed in the crystal structure of the lipopeptide:TLR2 complex; consequently, activity is lost in homologated compounds. Penicillamine-derived analogues are also inactive, likely due to unfavorable steric interactions with the carbonyl of Ser 12 in TLR2. The thioether in this chemotype can be replaced with a selenoether. Importantly, the thioglycerol motif can be dispensed with altogether and can be replaced with a thioethanol bridge. These results have led to a structurally simpler, synthetically more accessible, and water-soluble analogue possessing strong TLR2-agonistic activities in human blood.
authors: Department of Medicinal Chemistry, University of Kansas, Multidisciplinary Research Building, Lawrence, KS 66047, United States.
authors: Geetanjali
authors: G
authors: Agnihotri
authors: Breanna M
authors: BM
authors: Crall
authors: Tyler C
authors: TC
authors: Lewis
authors: Timothy P
authors: TP
authors: Day
authors: Rajalakshmi
authors: R
authors: Balakrishna
authors: Hemamali J
authors: HJ
authors: Warshakoon
authors: Subbalakshmi S
authors: SS
authors: Malladi
authors: Sunil A
authors: SA
authors: David
mesh_terms: D000276:Adjuvants, Immunologic / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D006801:Humans; D008041:Linoleic Acids / Q000138:chemical synthesis / Q000276:immunology / Q000494:pharmacology; D055666:Lipopeptides / Q000138:chemical synthesis* / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D051195:Toll-Like Receptor 2 / Q000819:agonists*; D017962:alpha-Linolenic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000276:immunology / Q000494:pharmacology
chemical_list: D000276:Adjuvants, Immunologic; D008041:Linoleic Acids; D055666:Lipopeptides; D051195:Toll-Like Receptor 2; D017962:alpha-Linolenic Acid