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

Autor: Verpalen ECJM; Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG, Utrecht, The Netherlands., Brouwer AJ; Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG, Utrecht, The Netherlands., Wolfert MA; Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG, Utrecht, The Netherlands.; Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA., Boons GJ; Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG, Utrecht, The Netherlands.; Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA.; Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands.; Chemistry Department, University of Georgia, Athens, GA 30602, USA.
Jazyk: angličtina
Zdroj: Chemistry (Weinheim an der Bergstrasse, Germany) [Chemistry] 2024 Jun 06; Vol. 30 (32), pp. e202400429. Date of Electronic Publication: 2024 May 06.
DOI: 10.1002/chem.202400429
Abstrakt: 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.
(© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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