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- Title
Structure‐Based Design and Synthesis of Lipid A Derivatives to Modulate Cytokine Responses.
- Authors
Verpalen, Enrico C. J. M.; Brouwer, Arwin J.; Wolfert, Margreet A.; Boons, Geert‐Jan
- 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.
- Subjects
TOLL-like receptor agonists; LIPID synthesis; IMMUNOMODULATORS; ESCHERICHIA coli; IMMUNOLOGICAL adjuvants; GLYCERYL ethers; LIPIDS; ETHER lipids
- Publication
Chemistry - A European Journal, 2024, Vol 30, Issue 32, p1
- ISSN
0947-6539
- Publication type
Article
- DOI
10.1002/chem.202400429