Chemical synthesis of Burkholderia Lipid?A modified with glycosyl phosphodiester-linked 4-amino-4-deoxy-?-L-arabinose and its immunomodulatory potential.

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-?-L-arabinose (?-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 ?-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 ?-L-Ara4N H-phosphonate to ?-lactol of ?(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, ?-L-Ara4N-substituted Burkholderia Lipid?A. The ?-L-Ara4N modification significantly enhanced the pro-inflammatory innate immune signaling of otherwise non-endotoxic Burkholderia Lipid?A.

SUBMITTER: Hollaus R 

PROVIDER: S-EPMC4517147 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature