Innate immune responses of synthetic lipid a derivatives of Neisseria meningitidis

Yanghui Zhang, Jidnyasa Gaekwad, Margreet A. Wolfert, Geert-Jan Boons

Research output: Contribution to journalArticleAcademicpeer-review


Differences in the pattern and chemical nature of fatty acids of lipid A of Neisseria meningitides lipooligosaccharides (LOS) and Escherichia coli lipopolysaccharides (LPS) may account for differences in inflammatory properties. Furthermore, there are indications that dimeric 3-deoxy-D-mannooct- 2-ulosonic acid (KDO) moieties of LOS and LPS enhance biological activities. Heterogeneity in the structure of lipid A and possible contaminations with other inflammatory components have made it difficult to confirm these observations. To address these problems, a highly convergent approach for the synthesis of a lipid A derivative containing KDO has been developed. which relies on the ability to selectively remove or unmask in a sequential manner an isopropylidene acetal, 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonate (Alloc), azide, and thexyldimethylsilyl (TDS) ether. The strategy was employed for the synthesis of N. meningitidis lipid A containing KDO (3). Mouse macrophages were exposed to the synthetic compound and its parent LOS, E. coli lipid A (2), and a hybrid derivative (4) that has the asymmetrical acylation pattern of E. coli lipid A, but the shorter lipids of meningococcal lipid A. The resulting supernatants were examined for tumor necrosis factor alpha (TNF-α) and interferon beta (IFN-β) production. The lipid A derivative containing KDO was much more active than lipid A alone and just slightly less active than its parent LOS, indicating that one KDO moiety is sufficient for full activity of TNF-α and IFN-β induction. The lipid A of N. meningitidis was a significantly more potent inducer of TNF-α and IFN-β than E. coli lipid A, which is due to a number of shorter fatty acids. The compounds did not demonstrate a bias towards a MyD88- or TRIF-dependent response. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA.
Original languageEnglish
Pages (from-to)558-569
Number of pages12
JournalChemistry - A European Journal
Issue number2
Publication statusPublished - 16 Jan 2008


  • Carbohydrates
  • Glycosylation
  • Immunology
  • Oligosaccharides
  • 3 deoxy manno octulosonic acid
  • beta interferon
  • drug derivative
  • lipid A
  • lipid linked oligosaccharides
  • lipid-linked oligosaccharides
  • lipopolysaccharide
  • sugar acid
  • tumor necrosis factor
  • animal
  • article
  • biosynthesis
  • chemical structure
  • chemistry
  • conformation
  • drug effect
  • Escherichia coli
  • immunological procedures
  • immunology
  • innate immunity
  • macrophage
  • mouse
  • Neisseria meningitidis
  • stereoisomerism
  • synthesis


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