Chemical Synthesis of Burkholderia Lipid A Modified with Glycosyl Phosphodiester‐Linked 4‐Amino‐4‐deoxy‐β‐L‐arabinose and Its Immunomodulatory Potential |
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Authors: | Dr Ralph Hollaus Dr Simon Ittig Dr Andreas Hofinger Mira Haegman Prof Rudi Beyaert Prof Paul Kosma Prof Alla Zamyatina |
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Institution: | 1. Department of Chemistry, University of Natural Resources and Life Sciences, Muthgasse?18, 1190 Vienna (Austria);2. Biozentrum, University of Basel, Klingelbergstrasse?50/70, 4056 Basel (Switzerland);3. Department for Biomedical Molecular Biology, Unit of Molecular Signal Transduction in Inflammation, Ghent University, Inflammation Research Center, VIB, Technologiepark?927, 9052 Ghent (Belgium) |
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Abstract: | Modification of the Lipid A phosphates by positively charged appendages is a part of the survival strategy of numerous opportunistic Gram‐negative bacteria. The phosphate groups of the cystic fibrosis adapted Burkholderia Lipid A are abundantly esterified by 4‐amino‐4‐deoxy‐β‐L ‐arabinose (β‐L ‐Ara4N), which imposes resistance to antibiotic treatment and contributes to bacterial virulence. To establish structural features accounting for the unique pro‐inflammatory activity of Burkholderia LPS we have synthesised Lipid A substituted by β‐L ‐Ara4N at the anomeric phosphate and its Ara4N‐free counterpart. The double glycosyl phosphodiester was assembled by triazolyl‐tris‐(pyrrolidinyl)phosphonium‐assisted coupling of the β‐L ‐Ara4N H‐phosphonate to α‐lactol of β(1→6) diglucosamine, pentaacylated with (R)‐(3)‐acyloxyacyl‐ and Alloc‐protected (R)‐(3)‐hydroxyacyl residues. The intermediate 1,1′‐glycosyl‐H‐phosphonate diester was oxidised in anhydrous conditions to provide, after total deprotection, β‐L ‐Ara4N‐substituted Burkholderia Lipid A. The β‐L ‐Ara4N modification significantly enhanced the pro‐inflammatory innate immune signaling of otherwise non‐endotoxic Burkholderia Lipid A. |
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Keywords: | carbohydrates glycolipids glycosyl phosphates lipopolysaccharide structure– activity relationships |
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