Synthesis of fragments of the capsular polysaccharide of Neisseria meningitidis (serogroup A) suitable for bioconjugation

  • Alan Black

    Student thesis: Doctoral ThesisDoctor of Philosophy


    One of the causative agents of meningitis is the gram-negative bacteria Neisseria meningitidis. In the region known as the African meningitis belt, N. meningitidis serotype A is endemic in the population and is also known to cause large scale epidemics. An important virulence factor of this bacterium is the presence of a capsular polysaccharide (CPS) and apart from being an important surface antigen, also protects the bacteria cells against phagocytosis by the host’s immune defense. The CPS structure of the serotype A is the (1-6)-linked poly(3-O-acetyl-2-acetamido-2-deoxy-a-D-mannosyl phosphate):
    A potential route towards a vaccine would be to synthetically produce fragments of the CPS. In order to synthesise these CPS structures (1), the monosaccharide precursors 2-5 must be prepared first with temporary protection of the O-6 position and a permanent protection at the O-4 position. Formation and elongation of the CPS oligomers proceeds through the condensation of anomeric H-phosphonates 6. In order to accommodate this, compounds 2-5 allow for hydrolysis at the position-1 to the corresponding hemi-acetals. These are then converted to the H-phosphonates 6 before coupling to a monohydroxyl unit (structures 8) to form a phosphodiester linkage. Removal of the temporary protection at O-6 then gives the free hydroxyl (structures 7) needed for the chain elongation to continue. The fragments then will be capped with ethanolamine H-phosphonate 9 that will allow for conjugation to a protein carrier.
    Date of Award2014
    Original languageEnglish
    SponsorsBiotechnology and Biological Sciences Research Council
    SupervisorAndrei Nikolaev (Supervisor)

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