Synthesis of haemophilus influenzae type a oligosaccharides

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Synthesis of haemophilus influenzae type a oligosaccharides

Claudia Kohout 1 , Luigi Lay 1

1 University of Milan, Department of Chemistry, Milan, Italy

The pathogen Haemophilus influenzae (Hi) is a major cause of severe diseases, i.e. meningitis, sepsis and otitis, especially affecting young children. Among 6 serotypes, type b (Hib) is the most common and most virulent strain. Additionally, Hib is the first successful example of a vaccine based on synthetic carbohydrate antigens licensed and distributed in Cuba since 2004 with the tradename QuimiHib. [1]

In recent years an increasing rate of infections caused by Hia raised some concern and currently, Hia causes up to 10 % of reported Haemophilus infections. This burden is steadily increasing, and no vaccine targeting Hia is currently available or under development. The capsular polysaccharide (CPS) of Hia is a polymer of 4-β-D-Glc-(1→4)-D-ribitol-5-(PO4→) repeating units and is a potential antigen for a future protein-conjugated polysaccharide vaccine. Furthermore, synthetic oligomers, such as 1 (Scheme 1), are valuable tools to identify a protective epitope within Hia CPS. [2,3]

In this communication we focus on the first described synthesis of oligomers with different chain length such as 1. Crucial and versatile building blocks (2 and 3) were synthesized and further coupled by using phosphoramidite approach. All synthesized oligomers contain a proper N-terminating linker suitable for further protein carrier conjugation. Different approaches and challenges for the oligomerization will be discussed.

Scheme 1 Retrosynthetic strategy to achieve oligomers of Hia CPS

Astronomo R.D., Burton D. R., Carbohydrate vaccines: developing sweet solutions to sticky situations? Nat. Rev. Drug. Discov. 2010, 9 (4), 308-24.

Ulanova M., Tsang R.S.W., Haemophilus influenzae serotype a as a cause of serious invasive infections. Lancet Infect. Dis. 2014, 14 (1), 70-82.

Jin Z., Romero-Steiner S., Carlone G.M., Robbins J.B., Schneerson R., Haemophilus influenzae Type a Infection and Its Prevention. Infect. Immun. 2007, 75 (6), 2650-2654.

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