Design and Synthesis of TLR2 and TLR6 Heterodimer Ligands, a Triply Functionalized α-GalCer Derivative for Identifying Proteins Involved in Glycolipid Trafficking, and the Disaccharide of Staphylococcus aureus CP8 Towards a Self-Adjuvanting Vaccine
Toll like receptors (TLRs) are found on B cells, macrophages, monocytes, and dendritic cells, and these cells belong to the innate immune system that recognizes antigens and induces multiple cell responses through the release of cytokines. TLR1, TLR2 and TLR6 function as heterodimers, either as TLR1/TLR2 or TLR2/TLR6 to recognize lipopeptides. TLR1/2 dimer activation releases inflammatory cytokines, while TLR2/TLR6 dimer activation releases immunomodulatory cytokines. Based on the size of the binding pocket between TLR2 and TLR6, it was hypothesized that lipopeptides, such as FSL1, could be simplified while keeping overall activity. FSL1 is a lipopeptide first isolated from Mycoplasma salivarum that activates macrophages at picomolar concentrations. It is expected that synthetic lipopeptides mimicking immunostimulatory molecules such as FSL1 will allow development of better ways to stimulate or modulate the immune system. Therefore, novel synthetic TLR2/6 ligands were synthesized replacing the polylysine chain with a polyamine chain showing activation of the immune cells in a manner like FSL1. Natural killer T-cell (NKT) antigens, such as α-galactosylceramide (α-GalCer), are carried through the body by lipid transfer proteins before they interact with the NKT cells. Not all the proteins involved in glycolipid transportation have been characterized. The synthesis of an α-GalCer analogue, termed CD1d-Triceps was designed to help find additional proteins involved in glycolipid trafficking. CD1d-Triceps has three functionalities: the first is the α-GalCer structure, and the other two are on C6 of the sugar: biotin, which helps tag the molecule for its purification, and a photoactive tag that, upon UV light activation, will cross-link with neighboring proteins. Antibiotic-resistant strains of Staphylococcus aureus (SA) are a growing health problem worldwide. Serotype 5 and 8 are the most common SA pathogens. Loading the serotype 5 or 8 disaccharides onto Qβ-particles that are linked to an NKT cell activator yield a vaccine that is expected to trigger adaptive immunity to the disaccharide. Previous similar studies showed production of antibodies with high affinity against Streptococcus pyogenes oligosaccharides in a similar vaccine.
College and Department
Physical and Mathematical Sciences; Chemistry and Biochemistry
BYU ScholarsArchive Citation
Mata, Sara Mayeth, "Design and Synthesis of TLR2 and TLR6 Heterodimer Ligands, a Triply Functionalized α-GalCer Derivative for Identifying Proteins Involved in Glycolipid Trafficking, and the Disaccharide of Staphylococcus aureus CP8 Towards a Self-Adjuvanting Vaccine" (2019). Theses and Dissertations. 7580.
immune system, NKT cell, adjuvant, glycolipid, synthesis, organic, chemistry, immunology, trafficking, carbohydrate, TLR2, TLR6, ligand, Q-β particle, Staphylococcus A, serotype, disaccharide, vaccine