title: Chemical synthesis of Burkholderia Lipid A modified with glycosyl phosphodiester-linked 4-amino-4-deoxy-β-L-arabinose and its immunomodulatory potential.
abstract: Modification of the Lipid A phosphates by positively charged appendages is a part of the survival strategy of numerous opportunistic Gram-negative bacteria. The phosphate groups of the cystic fibrosis adapted Burkholderia Lipid A are abundantly esterified by 4-amino-4-deoxy-β-L-arabinose (β-L-Ara4N), which imposes resistance to antibiotic treatment and contributes to bacterial virulence. To establish structural features accounting for the unique pro-inflammatory activity of Burkholderia LPS we have synthesised Lipid A substituted by β-L-Ara4N at the anomeric phosphate and its Ara4N-free counterpart. The double glycosyl phosphodiester was assembled by triazolyl-tris-(pyrrolidinyl)phosphonium-assisted coupling of the β-L-Ara4N H-phosphonate to α-lactol of β(1→6) diglucosamine, pentaacylated with (R)-(3)-acyloxyacyl- and Alloc-protected (R)-(3)-hydroxyacyl residues. The intermediate 1,1'-glycosyl-H-phosphonate diester was oxidised in anhydrous conditions to provide, after total deprotection, β-L-Ara4N-substituted Burkholderia Lipid A. The β-L-Ara4N modification significantly enhanced the pro-inflammatory innate immune signaling of otherwise non-endotoxic Burkholderia Lipid A.
authors: Department of Chemistry, University of Natural Resources and Life Sciences, Muthgasse 18, 1190 Vienna (Austria).
authors: Ralph
authors: R
authors: Hollaus
authors: Simon
authors: S
authors: Ittig
authors: Andreas
authors: A
authors: Hofinger
authors: Mira
authors: M
authors: Haegman
authors: Rudi
authors: R
authors: Beyaert
authors: Paul
authors: P
authors: Kosma
authors: Alla
authors: A
authors: Zamyatina
mesh_terms: D000606:Amino Sugars / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001089:Arabinose / Q000737:chemistry*; D001426:Bacterial Proteins / Q000737:chemistry; D019117:Burkholderia / Q000737:chemistry*; D004926:Escherichia coli / Q000737:chemistry*; D005944:Glucosamine / Q000737:chemistry; D006017:Glycolipids / Q000737:chemistry*; D006801:Humans; D008050:Lipid A / Q000138:chemical synthesis* / Q000737:chemistry* / Q000276:immunology; D008070:Lipopolysaccharides / Q000138:chemical synthesis* / Q000737:chemistry; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D000606:Amino Sugars; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D006017:Glycolipids; D008050:Lipid A; D008070:Lipopolysaccharides; C040134:4-amino-4-deoxyarabinose; D001089:Arabinose; D005944:Glucosamine
keywords: carbohydrates; glycolipids; glycosyl phosphates; lipopolysaccharide; structure-activity relationships
references: Chemistry. 2007;13(12):3501-11
references: 17219455
references: Proc Natl Acad Sci U S A. 2013 Jan 22;110(4):1464-9
references: 23297218
references: Chemistry. 2011 Dec 16;17(51):14464-74
references: 22095469
references: Nat Rev Microbiol. 2005 Feb;3(2):144-56
references: 15643431
references: Org Lett. 2014 Jul 18;16(14):3772-5
references: 25003818
references: PLoS Pathog. 2012;8(5):e1002667
references: 22570611
references: Annu Rev Biochem. 2007;76:295-329
references: 17362200
references: Chemistry. 2006 Aug 25;12(25):6692-700
references: 16807947
references: J Org Chem. 2001 Sep 21;66(19):6234-43
references: 11559168
references: J Infect Dis. 2007 Oct 1;196(7):1088-92
references: 17763333
references: Chemistry. 2015 Jan 7;21(2):500-19
references: 25353096
references: Acc Chem Res. 2002 Nov;35(11):952-60
references: 12437320
references: Synthesis (Stuttg). 2010 Sep;2010(18):3143-3151
references: 22187517
references: Chemistry. 2008;14(2):558-69
references: 17943705
references: Chembiochem. 2013 Jun 17;14(9):1105-15
references: 23733445
references: Innate Immun. 2010 Dec;16(6):354-65
references: 19880661
references: Nature. 2009 Apr 30;458(7242):1191-5
references: 19252480
references: Beilstein J Org Chem. 2014 Oct 13;10:2367-76
references: 25383107
references: Org Lett. 2013 Jan 18;15(2):342-5
references: 23293947
references: J Bacteriol. 2008 Jun;190(12):4281-90
references: 18424515
references: J Endotoxin Res. 2001;7(3):167-202
references: 11581570
references: Mol Microbiol. 2012 Sep;85(5):962-74
references: 22742453
references: Chem Rec. 2006;6(6):333-43
references: 17304523
references: J Biol Chem. 2010 Sep 17;285(38):29375-86
references: 20634284
references: Org Biomol Chem. 2005 Oct 21;3(20):3782-7
references: 16211114
references: Pure Appl Chem. 2011 Nov 19;84(1):11-21
references: 22942477
references: Glycobiology. 2005 May;15(5):561-70
references: 15610978
references: Innate Immun. 2008 Jun;14(3):127-44
references: 18562572
references: J Lipid Res. 2006 May;47(5):1097-111
references: 16479018
references: J Org Chem. 2006 Jun 9;71(12):4682-4
references: 16749807
references: Eur J Biochem. 1985 Apr 1;148(1):1-5
references: 2579812
references: Chemistry. 2003 Apr 4;9(7):1542-8
references: 12658652
references: Clin Vaccine Immunol. 2009 Oct;16(10):1420-8
references: 19692625
references: Mol Microbiol. 2007 Jan;63(2):379-90
references: 17163980
references: J Biol Chem. 2003 Jul 4;278(27):24731-9
references: 12704196
references: Chemistry. 2005 Apr 8;11(8):2493-504
references: 15729674
references: J Med Chem. 2014 Oct 9;57(19):8056-71
references: 25252784
references: Nat Rev Microbiol. 2013 Jul;11(7):467-81
references: 23748343
references: Am J Respir Crit Care Med. 2004 Jul 1;170(1):70-7
references: 15044201