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Chemical synthesis of Burkholderia Lipid A modified with glycosyl phosphodiester-linked 4-amino-4-deoxy-beta-L-arabinose and its immunomodulatory potential

(2015) CHEMISTRY-A EUROPEAN JOURNAL. 21(10). p.4102-4114
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Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
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-beta-L-arabinose (beta-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 beta-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 beta-L-Ara4N H-phosphonate to a-lactol of beta(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, beta-L-Ara4N-substituted Burkholderia Lipid A. The beta-L-Ara4N modification significantly enhanced the pro-inflammatory innate immune signaling of otherwise non-endotoxic Burkholderia Lipid A.
Keywords
glycosyl phosphates, glycolipids, carbohydrates, lipopolysaccharide, structure-activity relationships, PRO-INFLAMMATORY ACTIVITY, INNATE IMMUNE-RESPONSES, ESCHERICHIA-COLI, CAPSULAR POLYSACCHARIDE, NEISSERIA-MENINGITIDIS, STRUCTURAL-CHARACTERIZATION, EFFICIENT SYNTHESIS, CONDENSING REAGENT, PEPTIDE-SYNTHESIS, CEPACIA COMPLEX

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Citation

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MLA
Hollaus, Ralph et al. “Chemical Synthesis of Burkholderia Lipid A Modified with Glycosyl Phosphodiester-linked 4-amino-4-deoxy-beta-L-arabinose and Its Immunomodulatory Potential.” CHEMISTRY-A EUROPEAN JOURNAL 21.10 (2015): 4102–4114. Print.
APA
Hollaus, R., Ittig, S., Hofinger, A., Haegman, M., Beyaert, R., Kosma, P., & Zamyatina, A. (2015). Chemical synthesis of Burkholderia Lipid A modified with glycosyl phosphodiester-linked 4-amino-4-deoxy-beta-L-arabinose and its immunomodulatory potential. CHEMISTRY-A EUROPEAN JOURNAL, 21(10), 4102–4114.
Chicago author-date
Hollaus, Ralph, Simon Ittig, Andreas Hofinger, Mira Haegman, Rudi Beyaert, Paul Kosma, and Alla Zamyatina. 2015. “Chemical Synthesis of Burkholderia Lipid A Modified with Glycosyl Phosphodiester-linked 4-amino-4-deoxy-beta-L-arabinose and Its Immunomodulatory Potential.” Chemistry-a European Journal 21 (10): 4102–4114.
Chicago author-date (all authors)
Hollaus, Ralph, Simon Ittig, Andreas Hofinger, Mira Haegman, Rudi Beyaert, Paul Kosma, and Alla Zamyatina. 2015. “Chemical Synthesis of Burkholderia Lipid A Modified with Glycosyl Phosphodiester-linked 4-amino-4-deoxy-beta-L-arabinose and Its Immunomodulatory Potential.” Chemistry-a European Journal 21 (10): 4102–4114.
Vancouver
1.
Hollaus R, Ittig S, Hofinger A, Haegman M, Beyaert R, Kosma P, et al. Chemical synthesis of Burkholderia Lipid A modified with glycosyl phosphodiester-linked 4-amino-4-deoxy-beta-L-arabinose and its immunomodulatory potential. CHEMISTRY-A EUROPEAN JOURNAL. 2015;21(10):4102–14.
IEEE
[1]
R. Hollaus et al., “Chemical synthesis of Burkholderia Lipid A modified with glycosyl phosphodiester-linked 4-amino-4-deoxy-beta-L-arabinose and its immunomodulatory potential,” CHEMISTRY-A EUROPEAN JOURNAL, vol. 21, no. 10, pp. 4102–4114, 2015.
@article{5930077,
  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-beta-L-arabinose (beta-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 beta-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 beta-L-Ara4N H-phosphonate to a-lactol of beta(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, beta-L-Ara4N-substituted Burkholderia Lipid A. The beta-L-Ara4N modification significantly enhanced the pro-inflammatory innate immune signaling of otherwise non-endotoxic Burkholderia Lipid A.},
  author       = {Hollaus, Ralph and Ittig, Simon and Hofinger, Andreas and Haegman, Mira and Beyaert, Rudi and Kosma, Paul and Zamyatina, Alla},
  issn         = {0947-6539},
  journal      = {CHEMISTRY-A EUROPEAN JOURNAL},
  keywords     = {glycosyl phosphates,glycolipids,carbohydrates,lipopolysaccharide,structure-activity relationships,PRO-INFLAMMATORY ACTIVITY,INNATE IMMUNE-RESPONSES,ESCHERICHIA-COLI,CAPSULAR POLYSACCHARIDE,NEISSERIA-MENINGITIDIS,STRUCTURAL-CHARACTERIZATION,EFFICIENT SYNTHESIS,CONDENSING REAGENT,PEPTIDE-SYNTHESIS,CEPACIA COMPLEX},
  language     = {eng},
  number       = {10},
  pages        = {4102--4114},
  title        = {Chemical synthesis of Burkholderia Lipid A modified with glycosyl phosphodiester-linked 4-amino-4-deoxy-beta-L-arabinose and its immunomodulatory potential},
  url          = {http://dx.doi.org/10.1002/chem.201406058},
  volume       = {21},
  year         = {2015},
}

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