Spotlight #2, Radhika Rani
Immunoactivity of Protein Conjugates of Carba Analogues from Neisseria meningitidis A Capsular Polysaccharide
ACS Chem. Biol., 2013, 8 (11), pp 2561–2567
Of the 1,200,000 cases of meningitis reported annually, up to 20% of the total cases that occur in developing countries are often fatal, whereas in industrialized countries this figure is only around 5-10%. Although this statistic within itself is quite daunting, a directly related issue that is often problematic is the effective transport of vaccines in poor countries. Because of the poor hydrolytic stability of the MenA capsular polysaccharide (CPS), delivery of the vaccine relies on the ‘cold chain’ system, which refers to the distribution network during which optimal temperatures are maintained during transport and handling. Therefore, failures in this network not only result in costly waste, but also compromise the integrity of the vaccine. Thus, Gao et al. attempt to address this obstacle by investigating the design and synthesis of hydrolytically stable analogues of MenA CPS.
Prior studies have reported the synthesis of phosphonoester-linked oligomers of MenA CPS as nonhydrolyzable analogues of glycosyl 1-O-phosphates, and it has also been determined that stabilization of glycosyl 1-O-phosphates can be achieved using carbasugar analogues as well. In their own studies, Gao et al. themselves observed that carba-N-acetylmannosamine-1-O-phosphate exhibits conformational behavior that is similar to that of naturally occurring N-acetylmannosamine-O-phosphate. This suggested that the species can act as a potential mimic of a MenA CPS repeating unit and led to the synthesis of carba oligomers (monomers, dimers, and trimers) that exhibited enhanced stability in comparison to the native polymer. A competitive ELIZA assay confirmed the success of the oligomers in inhibiting the binding between the native MenA CPS and a polyclonal anti-MenA serum. As a second stage of their investigation, the authors report on the immunological profile of the MenA carba analogues by studying the chemical conjugation of the compounds to the protein carrier CRM197. Following confirmation of conjugation via SDS-PAGE, immunological evaluation of the conjugates was performed using a mouse model. The immunization results allowed the authors to conclude that although all of the synthesized glycoconjugates led to the production of antibodies specifically directed to the carbasugars, only the conjugated trimer produced anti-MenA polysaccharide antibodies with in vitro bactericidal activity. Thus, Gao et al. were successful in demonstrating the first proof-of-concept that structural mimics of naturally occurring antigens could be employed in preventative antimicrobrial therapy.