Structure‐Based Design and Synthesis of Lipid A Derivatives to Modulate Cytokine Responses
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.
- Location
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Deutsche Nationalbibliothek Frankfurt am Main
- Extent
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Online-Ressource
- Language
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Englisch
- Bibliographic citation
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Structure‐Based Design and Synthesis of Lipid A Derivatives to Modulate Cytokine Responses ; day:06 ; month:05 ; year:2024 ; extent:18
Chemistry - a European journal ; (06.05.2024) (gesamt 18)
- Creator
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Verpalen, Enrico C. J. M.
Brouwer, Arwin J.
Wolfert, Margreet A.
Boons, Geert‐Jan
- DOI
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10.1002/chem.202400429
- URN
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urn:nbn:de:101:1-2405071406434.390353714161
- Rights
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
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14.08.2025, 10:49 AM CEST
Data provider
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Associated
- Verpalen, Enrico C. J. M.
- Brouwer, Arwin J.
- Wolfert, Margreet A.
- Boons, Geert‐Jan
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