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Synthesis and Biological Evaluation of Phosphono Analogues of Capsular Polysaccharide Fragments from Neisseria meningitidis A
Author(s) -
TorresSanchez Maria I.,
Zaccaria Cristina,
Buzzi Benedetta,
Miglio Gianluca,
Lombardi Grazia,
Polito Laura,
Russo Giovanni,
Lay Luigi
Publication year - 2007
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200601743
Subject(s) - neisseria meningitidis , chemistry , phosphonate , stereochemistry , glycosyl , anomer , polysaccharide , neisseria , moiety , biochemistry , combinatorial chemistry , bacteria , biology , genetics
Abstract Neisseria meningitidis type A (MenA) is a Gram‐negative encapsulated bacterium that may cause explosive epidemics of meningitis, especially in the sub‐Saharan region of Africa. The development and manufacture of an efficient glycoconjugate vaccine against Neisseria meningitidis A is greatly hampered by the poor hydrolytic stability of its capsular polysaccharide, which is made up of (1→6)‐linked 2‐acetamido‐2‐deoxy‐α‐ D ‐mannopyranosyl phosphate repeating units. Since this chemical lability is a product of the inherent instability of the phosphodiester bridges, here we report the synthesis of phosphonoester‐linked oligomers of N ‐acetyl mannosamine as candidates for stabilised analogues of the corresponding phosphate‐bridged saccharides. The installation of each interglycosidic phosphonoester linkage was achieved by Mitsunobu coupling of a glycosyl C ‐phosphonate building block with the 6‐OH moiety of a mannosaminyl residue. Each of the synthesised compounds contains an O ‐linked aminopropyl spacer at its reducing end (α‐ or β‐oriented) to allow for protein conjugation. The relative affinities of the synthetic molecules were investigated by a competitive ELISA assay and showed that a human polyclonal anti‐MenA serum can recognise both the phosphonoester‐bridged fragments 1 – 3 and their monomeric subunits, glycosides 20 and 21 . Moreover, the biological results suggest that the abilities of these compounds to inhibit the binding of a specific antibody to MenA polysaccharide are dependent on the chain lengths of the molecules, but independent on the orientations of the anomeric linkers.