Synthesis of lactose-containing structures for development of drug and vaccine candidates

Bacteria, as well as several important human pathogenic viruses and fungi, such as Candida, Cryptococcus, Aspergillus, and HIV display surface carbohydrates, which can be important for shielding from the host’s immune system. They can be directly involved in virulence, and often contain antigens recognised by the hosts immune system. The surfaces of all eukaryotic cells are covered with the carbohydrate-containing glycocalyx, which controls or is involved in a wide variety of functions, such as fluid exchange, biomechanical sensing, protein binding, cell attachment, blood coagulation, and inflammation. The high level of complexity and variability in the glycocalyx in animals gives it a high potential for information storage, similar to that of other post-translational modifications of proteins, and to that of nucleotides and peptides. Lectins, non-enzymatic carbohydrate-binding proteins, are the main interpreters of the information stored in the glycocalyx. The common denominator of the projects in this thesis is lactose. As part of the BiOrbic bioeconomy research initiative, either lactose is utilised as a low-value renewable starting material for the synthesis of higher-value products, or the target structures themselves are synthesised as tools to investigate lactose’s role as an information carrier. The first project concerns the synthesis of the lactose-, and N-acetyllactosamie containing dodecasaccharide that is the trimer of the repeating unit of the capsular polysaccharide of Streptococcus pneumoniae serotype 14. S. pneumoniae S14 is a common human pathogen, and the structure is synthesised partly to show the feasibility of a synthetic approach towards a conjugate vaccine against the microorganism, but also for the possibility to determine the minimal protective epitope in humans, to identify S14-specific functional human antibodies, as well as to develop an assay-based, quick S14-specific test, which could be used in a clinical setting to identify S. pneumoniae S14 infections. The second project concerns the synthesis of four deoxy-fluorinated, selenium-containing pseudolactosides and galactosides, for the use as substrates in carbohydrate-lectin interaction studies. This to further the knowledge of the function-, and binding specificity of lectins. The final project concerns the synthesis of a dithio-lactoside, for the potential use as a mucolytic for the threatment of symptoms in CF-, COPD-, and severe asthma patients, and as a potential therapeutic for the threatment of SARS-CoV-2 infections.