SYNTHESIS AND STRUCTURAL DESIGN OF CARBOHYDRATE-BASED ARCHITECTURES: FROM VACCINE ADJUVANTS TO GLYCAN FOLDAMERS

Carbohydrates are complex molecules currently under deep investigation for the multiple roles they have in Nature: from source of energy, bricks of cell surface to several biological processes1. In the past years carbohydrates have been used in many applications: in the pharmaceutical field they are found in drug discovery2, design and synthesis of glycomimetics structures3, vaccine adjuvants4. Polyglycan structures have been used both for biology and for material chemistry purpose5. The first chapter of this PhD thesis focus the attention on vaccine adjuvant semi-synthesis. Vaccines are one of the oldest treatments in medicine prevention, since the first vaccination was performed in the 1790s by Edward Jenner for the cowpox prevention6. Science has made great strides over the last two centuries however, for many years vaccination relied on whole-pathogen approach exploiting: viral vector, live-attenuated vector or inactivated/killed vector to generate immunological response7. Although whole-pathogen vaccines elicit long-lasting immunity, safety issues related to administering these complex mixtures, prevent their universal application8; therefore, in the early 2000s, modern subunit vaccination were deeply investigated due to their improved safety and more precise targeting compared to whole-pathogen vaccination, as possible alternative9. Nevertheless, immunization with purified protein antigen (subunit) are inherently less immunogenic, typically resulting in a modest antibody response with little or no T cell response10. Adjuvants, in the context of vaccines, are defined as substances capable to enhance antigen-specific immune responses by triggering and modulating both the innate and acquired immunity: memory of long-lasting10. However, despite many years of improvements and developments, only few adjuvants are currently included in vaccination approved for human use: aluminium salts, emulsions (e.g. squalene), liposomes/virosomes and microparticles just to mention a few11. In this scenario, new classes of adjuvants are currently under investigation to offer an alternative and overcome this issue. Among them QS-21, an immunostimulatory saponin natural product extracted form Quillja Saponaria tree bark9, has emerged as a noteworthy alternative. The semi-synthesis of QS-21 and its main components will be faced in the first chapter of this thesis.