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Issue 13, 2007
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Agonistic and antagonistic properties of a Rhizobium sin-1 lipid A modified by an ether-linked lipid

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Abstract

LPS from Rhizobiumsin-1 (R.sin-1) can antagonize the production of tumor necrosis factor alpha (TNF-α) by E. coli LPS in human monocytic cells. Therefore these compounds provide interesting leads for the development of therapeutics for the prevention or treatment of septic shock. Detailed structure activity relationship studies have, however, been hampered by the propensity of these compounds to undergo β-elimination to give biological inactive enone derivatives. To address this problem, we have chemically synthesized in a convergent manner a R.sin-1 lipid A derivative in which the β-hydroxy ester at C-3 of the proximal sugar unit has been replaced by an ether linked moiety. As expected, this derivative exhibited a much-improved chemical stability. Furthermore, its ability to antagonize TNF-α production induced by enteric LPS was only slightly smaller than that of the parent ester modified derivative demonstrating that the ether-linked lipids affect biological activities only marginally. Furthermore, it has been shown for the first time that R.sin-1 LPS and the ether modified lipid A are also able to antagonize the production of the cytokine interferon-inducible protein 10, which arises from the TRIF-dependent pathway. The latter pathway was somewhat more potently inhibited than the MyD88-dependent pathway. Furthermore, it was observed that the natural LPS possesses much greater activity than the synthetic and isolated lipid As, which indicates that di-KDO moiety is important for optimal biological activity. It has also been found that isolated R.sin-1 LPS and lipid A agonize a mouse macrophage cell line to induce the production of TNF-α and interferon beta in a Toll-like receptor 4-dependent manner demonstrating species specific properties.

Graphical abstract: Agonistic and antagonistic properties of a Rhizobium sin-1 lipid A modified by an ether-linked lipid

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Publication details

The article was received on 23 Mar 2007, accepted on 17 May 2007 and first published on 29 May 2007


Article type: Paper
DOI: 10.1039/B704427E
Citation: Org. Biomol. Chem., 2007,5, 2087-2097

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    Agonistic and antagonistic properties of a Rhizobium sin-1 lipid A modified by an ether-linked lipid

    M. Vasan, M. A. Wolfert and G. Boons, Org. Biomol. Chem., 2007, 5, 2087
    DOI: 10.1039/B704427E

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