Conformationally constrained Lipid A mimetics for exploration of structural basis of TLR4/MD-2 activation by lipopolysaccharide

Artner, Daniel and Oblak, Alja and Ittig, Simon and Garate, Jose Antonio and Horvat, Simon and Arrieumerlou, Cécile and Hofinger, Andreas and Oostenbrink, Chris and Jerala, Roman and Kosma, Paul and Zamyatina, Alla. (2013) Conformationally constrained Lipid A mimetics for exploration of structural basis of TLR4/MD-2 activation by lipopolysaccharide. ACS chemical biology, Vol. 15, H. 8. pp. 2423-2432.

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Official URL: http://edoc.unibas.ch/dok/A6165331

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Recognition of the lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria, by the Toll-like receptor 4 (TLR4)-myeloid differentiation factor 2 (MD-2) complex is essential for the control of bacterial infection. A pro-inflammatory signaling cascade is initiated upon binding of membrane-associated portion of LPS, a glycophospholipid Lipid A, by a co-receptor protein MD-2, which results in a protective host innate immune response. However, activation of TLR4 signaling by LPS may lead to the dysregulated immune response resulting in a variety of inflammatory conditions including sepsis syndrome. Understanding of structural requirements for Lipid A endotoxicity would ensure the development of effective anti-inflammatory medications. Herein we report on design, synthesis and biological activities of a series of conformationally confined Lipid A mimetics based on β,α-trehalose-type scaffold. Replacement of the flexible three-bond β(1→6) linkage in diglucosamine backbone of Lipid A by a two-bond β,α(1↔1) glycosidic linkage afforded novel potent TLR4 antagonists. Synthetic tetraacylated bisphosphorylated Lipid A mimetics based on a β-GlcN(1↔1)α-GlcN scaffold selectively block the LPS binding site on both human and murine MD-2 and completely abolish lipopolysaccharide-induced pro-inflammatory signaling, thereby serving as antisepsis drug candidates. In contrast to their natural counterpart lipid IVa, conformationally constrained Lipid A mimetics do not activate mouse TLR4. The structural basis for high antagonistic activity of novel Lipid A mimetics was confirmed by molecular dynamics simulation. Our findings suggest that besides the chemical structure, also the three-dimensional arrangement of the diglucosamine backbone of MD-2-bound Lipid A determines endotoxic effects on TLR4.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Molecular Microbiology (Arrieumerlou)
UniBasel Contributors:Arrieumerlou, Cécile and Ittig, Simon Josef
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Chemical Society
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:18 Jul 2014 09:10
Deposited On:31 Jan 2014 09:49

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