title: Improving the immunostimulatory potency of diethanolamine-containing lipid A mimics.
abstract: Lipid A is the active principal of gram negative bacterial lipopolysaccharide (LPS) in the activation of Toll-like receptor 4 (TLR4). Given the important role TLR4 plays in innate immunity and the development of adaptive immune responses, ligands that can modulate TLR4-mediated signaling have great therapeutic potential. Recently, we have reported a series of monophosphorylated lipid A mimics as potential ligands of TLR4, in which a diethanolamine moiety is employed to replace the reducing end (d-glucosamine). In this paper, we describe the synthesis of two further diethanolamine-containing lipid A mimics, 3 and 4, in an effort to mimic more closely the di-phosphate nature of natural lipid A. Both mimic 3, with an additional phosphate on the diethanolamine acyclic scaffold, and mimic 4, with a terminal carboxylic acid moiety as a phosphate bioisostere, serve to increase the potency of the immunostimulatory response induced, as measured by the induction of the cytokines TNF-α, IL-6, and IL-1β in the human monocytic cell line THP-1. In addition, mechanistic studies involving the known TLR4 antagonist lipid IVa confirm TLR4 as the target of the diethanolamine-containing lipid A mimics.
authors.affiliation: Department of Chemistry, Lakehead University, 955 Oliver Road, Thunder Bay, Ontario, Canada P7B 5E1.
authors.forename: Jordan D
authors.initials: JD
authors.lastname: Lewicky
authors.affiliation: Medical Sciences Division, Northern Ontario School of Medicine, Lakehead University, 955 Oliver Road, Thunder Bay, Ontario, Canada P7B 5E1.
authors.forename: Marina
authors.initials: M
authors.lastname: Ulanova
authors.affiliation: Department of Chemistry, Lakehead University, 955 Oliver Road, Thunder Bay, Ontario, Canada P7B 5E1. Electronic address: zjiang@lakeheadu.ca.
authors.forename: Zi-Hua
authors.initials: ZH
authors.lastname: Jiang
mesh_terms: D000276:Adjuvants, Immunologic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004983:Ethanolamines / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D008050:Lipid A / Q000031:analogs & derivatives* / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D010766:Phosphorylation; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D004983:Ethanolamines; D008050:Lipid A; D051197:Toll-Like Receptor 4; C020283:diethanolamine