- Oligosaccharides derived from ribose-ribitol-phosphate, and vaccines containing them
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The present invention relates to the field of the Medicine, in particular with the chemical synthesis of oligosaccharide mixtures derived of ribose-ribitol-phosphate, which are used as active principle in vaccines for the prevention of infections caused byHaemophilus influenzaetype b (Hib), as well as with the vaccines containing said oligosaccharide mixtures. The oligasaccharide mixtures obtained by chemical synthesis of the present invention, comprise repeating units of formulae (phosphate-ribosa-ribitol)n or (ribose-ribitol-phosphate)n of at least 5 compounds of structure A or B, which represent the repeating unit of the capsular polysaccharide ofHaemophilus influenzaetype b and differ only by n, being n a value contained between 4 and 25 (n≧4 y≦25), and wherein R1or R2is a spacer for conjugation to a carrier, with the condition of R1=spacer if R2=H, or R2=spacer if R1=H. The invention also is related with the immunogens containing such oligosaccharide mixtures, with the vaccines containing said immunogens and with the methods to prepare these oligosaccharides as mixtures. Furthermore, the invention includes the use of the vaccines, alone or combined with other vaccines, for the prevention of the infections caused byHaemophilus influenzaetype b.
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Page column 20
(2010/02/07)
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- Determination of the configuration of ribitol in the C-polysaccharide of Streptococcus pneumoniae using a synthetic approach
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The C-polysaccharide is an antigen common to all known serotypes of Streptococcus pneumoniae bacteria and is a potential target for vaccine preparation. The final uncertainty in the structure of its repeating unit, a pentasaccharide phosphate containing two phosphorylcholine side chains, has been resolved by determining the configuration of ribitol. Assignment of configuration was performed by synthesis of the two trisaccharide phosphate fragments that have either D- or L-ribitol at their centers and comparison of their 1H and 13C NMR spectral data with that of the natural polysaccharide. The syntheses employed common synthons added in different orders to an asymmetrically substituted chiral ribitol derivative to obtain opposite chiralities in the ribitol segments. The data for the trisaccharide containing D-ribitol was almost identical to that of the natural material while that for the trisaccharide containing L-ribitol differed significantly. In particular, the chemical shift differences between the two protons of the primary carbons of ribitol units directly attached to the β-2-acetamido-2-deoxy-galactopyranosyl residue were 0.10, 0.12, and 0.33 ppm, in the natural polysaccharide, the D-ribitol-containing trisaccharide, and the L-ribitol-containing trisaccharide, respectively. The average difference between the 13C NMR chemical shifts of corresponding ribitol carbons from the natural polysaccharide and the D-ribitol-containing trisaccharide phosphate was 0.034 ppm. This evidence indicates that ribitol in the C-polysaccharide has the D-configuration and that a very similar mixture of conformations in the ribitol portions is present for the natural polysaccharide and the D-ribitol-containing trisaccharide phosphate.
- Qin, Huiping,Grindley, T. Bruce
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p. 481 - 494
(2007/10/03)
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- Novel polysaccharides novel macromolecular conjugates of the polysaccharides
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Synthesis of oligomeric subunits of the poly(ribosyl-ribitol-phosphate) capsular polysaccharide found on Haemophilus influenzaetype b bacteria. The covalent attachment of these compounds to immunogenic proteins without using spacer elements.
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- The synthesis of two repeating units of Haemophilus influenzae type a capsular antigen.
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The repeating units 2-O-beta-D-glucopyranosyl-L-ribitol 4'- and 1-phosphate of Haemophilus influenzae type a capsular antigen have been synthesised by condensation of an alpha-D-glucopyranosyl bromide derivative with 5-O-allyl-1,2,3-tri-O-benzyl-D-ribitol followed by selective deprotection of HO-4' or HO-1, phosphorylation, and removal of the blocking groups.
- Grzeszczyk,Banaszek,Zamojski
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p. 215 - 226
(2007/10/02)
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- A NEW APPROACH TO THE SYNTHESIS OF A DIMERIC FRAGMENT OF THE CAPSULAR POLYSACCHARIDE OF HAEMOPHILUS INFLUENZAE type b
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The synthesis of the monomeric fragment of the Haemophilus influenzae type b (HIb) polysaccharide starting from orthoacetate 7 is described.The construction of the dimer is also reported.
- Chan, Laval,Just, George
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p. 4049 - 4052
(2007/10/02)
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- SYNTHESIS OF FRAGMENTS OF THE CAPSULAR POLYSACCHARIDE OF HAEMOPHILUS INFLUENZAE TYPE B, COMPRISING TWO OR THREE REPEATING UNITS
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The synthesis of the ribosyl-ribitol derivatives 15 and 17 (Scheme 2) is presented.The compounds served as building blocks for the preparation of protected fragments (24, n=1 or 2; Fig. 2) of the title polysaccharide.The bifunctional reagent bis-2-chlorophenylphosphate (18, Fig. 2) was used for all phosphorylation reactions.Attachment to a spacer and complete deprotection of the products, to afford 25 (n=2 or 3), is described.
- Hoogerhout, P.,Evenberg, D.,Boeckel, C. A. A. van,Poolman, J. T.,Beuvery, E. C.,et al.
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p. 1553 - 1556
(2007/10/02)
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- Synthesis of fragments of the capsular polysaccharide of Haemophilus influenzae type b. Part I. Preparation of suitably protected 1-O-β-d-ribofuranosyl-d-ribitol building blocks
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The synthesis of the protected ribosylribitol derivatives 15 and 17, which are building blocks for the preparation of fragments of the H. influenzae type b polysaccharide, is presented. Starting from d-ribonolactone (1), 5-O-allyl-2,3,4-tri-O-benzyl-d-ribitol (8) was prepared in seven steps (Scheme 1). Coupling of 8 with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-d-ribofuranose (9) in the presence of trimethylsilyl trifluoromethanesulfonate gave the ribosylribitol derivative 10 (Scheme 2), which was debenzoylated to afford compound 11. The C-3′- and C-5′-hydroxyl functions of the ribose moiety of 11 were protected with the 1,1,3,3-tetraisopropyldisiloxane-1,3-diyl group and the C-2′ position with the benzyloxymethyl group. Compound 13 thus obtained was converted into its 5-O-trans-1-propenyl isomer 14. Cleavage of the propenyl group from 14 gave compound 15, which can be phosphorylated at O-5 of the ribitol. On the other hand, removal of the 3′,5′-protection from 14 and subsequent blocking of the primary hydroxyl function yielded ribosylribitol derivative 17 having a 3′-hydroxyl function available for phosphorylation.
- Hermans,Poot,Kloosterman,van der Marel,van Boeckel,Evenberg,Poolman,Hoogerhout,van Boom
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p. 498 - 504
(2007/10/02)
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