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

  • Alan Black

    Student thesis: Doctoral ThesisDoctor of Philosophy

    Abstract

    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)

    Cite this

    Synthesis of fragments of the capsular polysaccharide of Neisseria meningitidis (serogroup A) suitable for bioconjugation
    Black, A. (Author). 2014

    Student thesis: Doctoral ThesisDoctor of Philosophy