title: Characterization of TRIF selectivity in the AGP class of lipid A mimetics: role of secondary lipid chains.
abstract: TLR4 agonists that favor TRIF-dependent signaling and the induction of type 1 interferons may have potential as vaccine adjuvants with reduced toxicity. CRX-547 (4), a member of the aminoalkyl glucosaminide 4-phosphate (AGP) class of lipid A mimetics possessing three (R)-3-decanoyloxytetradecanoyl groups and d-relative configuration in the aglycon, selectively reduces MyD88-dependent signaling resulting in TRIF-selective signaling, whereas the corresponding secondary ether lipid 6a containing (R)-3-decyloxytetradecanoyl groups does not. In order to determine which secondary acyl groups are important for the reduction in MyD88-dependent signaling activity of 4, the six possible ester/ether hybrid derivatives of 4 and 6a were synthesized and evaluated for their ability to induce NF-κB in a HEK293 cell reporter assay. An (R)-3-decanoyloxytetradecanoyl group on the 3-position of the d-glucosamine unit was found to be indispensable for maintaining low NF-κB activity irrespective of the substitutions (decyl or decanoyl) on the other two secondary positions. These results suggest that the carbonyl group of the 3-secondary lipid chain may impede homodimerization and/or conformational changes in the TLR4-MD2 complex necessary for MyD88 binding and pro-inflammatory cytokine induction.
authors.affiliation: GlaxoSmithKline Vaccines, 553 Old Corvallis Road, Hamilton, MT 59840, USA.
authors.forename: Juhienah K
authors.initials: JK
authors.lastname: Khalaf
authors.affiliation: Institute for Cellular Therapeutics, University of Louisville School of Medicine, Donald E. Baxter Biomedical Research Building, 570 South Preston Street, Louisville, KY 40202, USA.
authors.forename: William S
authors.initials: WS
authors.lastname: Bowen
authors.affiliation: GlaxoSmithKline Vaccines, 553 Old Corvallis Road, Hamilton, MT 59840, USA.
authors.forename: Hélène G
authors.initials: HG
authors.lastname: Bazin
authors.affiliation: GlaxoSmithKline Vaccines, 553 Old Corvallis Road, Hamilton, MT 59840, USA.
authors.forename: Kendal T
authors.initials: KT
authors.lastname: Ryter
authors.affiliation: GlaxoSmithKline Vaccines, 553 Old Corvallis Road, Hamilton, MT 59840, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Livesay
authors.affiliation: GlaxoSmithKline Vaccines, 553 Old Corvallis Road, Hamilton, MT 59840, USA.
authors.forename: Jon R
authors.initials: JR
authors.lastname: Ward
authors.affiliation: GlaxoSmithKline Vaccines, 553 Old Corvallis Road, Hamilton, MT 59840, USA.
authors.forename: Jay T
authors.initials: JT
authors.lastname: Evans
authors.affiliation: GlaxoSmithKline Vaccines, 553 Old Corvallis Road, Hamilton, MT 59840, USA. Electronic address: david.a.johnson@gsk.com.
authors.forename: David A
authors.initials: DA
authors.lastname: Johnson
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D001672:Biocompatible Materials / Q000737:chemistry / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D005944:Glucosamine / Q000031:analogs & derivatives / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D008050:Lipid A / Q000737:chemistry*; D062105:Molecular Docking Simulation; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000378:metabolism
chemical_list: C530112:AGP 527; D033942:Adaptor Proteins, Vesicular Transport; D001672:Biocompatible Materials; D016207:Cytokines; D008050:Lipid A; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D009943:Organophosphorus Compounds; C470409:TICAM1 protein, human; D051197:Toll-Like Receptor 4; D005944:Glucosamine
keywords: AGP; Glycolipids; Lipid A mimetic; NF-κB activity; TLR4 agonist; TRIF selectivity; Vaccine adjuvant