Structure-Based Design and Synthesis of Lipid A Derivatives to Modulate Cytokine Responses

Enrico C J M Verpalen, Arwin J Brouwer, Margreet A Wolfert, Geert-Jan Boons*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Agonists of Toll like receptors (TLRs) have attracted interest as adjuvants and immune modulators. A crystal structure of TLR4/MD2 with E. coli LPS indicates that the fatty acid at C-2 of the lipid A component of LPS induces dimerization of two TLR4-MD2 complexes, which in turn initiates cell signaling leading to the production of (pro)inflammatory cytokines. To probe the importance of the (R)-3-hydroxymyristate at C-2 of lipid A, a range of bis- and mono-phosphoryl lipid A derivatives with different modifications at C-2 were prepared by a strategy in which 2-methylnaphthyl ethers were employed as permanent protecting group that could be readily removed by catalytic hydrogenation. The C-2 amine was protected as 9-fluorenylmethyloxycarbamate, which at a later stage could be removed to give a free amine that was modified by different fatty acids. LPS and the synthetic lipid As induced the same cytokines, however, large differences in activity were observed. A compound having a hexanoyl moiety at C-2 still showed agonistic properties, but further shortening to a butanoyl abolished activity. The modifications had a larger influence on monophosphoryl lipid As. The lipid As having a butanoyl moiety at C-2 could selectively antagonize TRIF associated cytokines induced by LPS or lipid A.

Original languageEnglish
Article numbere202400429
JournalChemistry-A European Journal
Volume30
Issue number32
Early online date8 Apr 2024
DOIs
Publication statusPublished - 6 Jun 2024

Keywords

  • adjuvant
  • cytokines
  • glycolipid
  • glycosylation
  • immune modulation

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