Synthesis of Peptidoglycan Fragments to Probe the Chemical Biology of the Innate Immune System
| Author(s) | Ramsey, Jared | |
| Date Accessioned | 2022-06-16T16:08:04Z | |
| Date Available | 2022-06-16T16:08:04Z | |
| Publication Date | 2021-05 | |
| Abstract | The bacterial cell wall, comprised of peptidoglycan (PG), is a key tool for the identification of bacteria by the innate immune system. For the body to function properly, this system needs to be able to accurately dispose of pathogenic threats while retaining commensal bacteria. To accomplish this, immune receptors can recognize PG from a variety of bacterial species and differentiate between them. Unfortunately, errors are known to occur in this recognition, leading to false inflammatory responses. For many people, this occurs in the gut, resulting in inflammatory bowel diseases (IBD’s). The immune proteins NOD1 and NOD2 (nucleotide oligomerization binding proteins) have been found to bind PG fragments known as muramyl dipeptide (MDP), and iE-DAP respectively. Both are PG derived ligands which have been studied frequently. However, when bacteria are digested in the body, PG can fragment into a diverse pool of structures. It’s important to have an expansive set of chemical tools which allow for the investigation of innate immune response with various PG fragments. Here, synthesis was focused on obtaining a library of muramyl dimers linked through their peptide chain, a class of compounds whose properties have been scarcely studied. The synthesis of lysine crosslinked dimers was previously displayed in our lab using solid phase techniques. This work expands on the aforementioned synthesis by implementing meso-diaminopimelic acid (m-DAP) crosslinking patterns which are characteristic to Gram-negative bacteria. Furthermore, a solution phase approach has been devised. The completed synthesis of these compounds will open the doors to an array of applications for muramyl dimers, one such being their use in qRT-PCR assays. Furthermore, synthetic efforts were also directed toward the creation of an alkyne linked MDP derivative. Through previously developed methyl N,O,-hydroxylamine linker chemistries, successful synthesis of this compound will allow for rapid functionalization of MDP. | en_US |
| Advisor | Catherine Leimkuhler Grimes | |
| Program | Biochemistry | |
| URL | https://udspace.udel.edu/handle/19716/30994 | |
| Publisher | University of Delaware | en_US |
| Keywords | Synthesis | en_US |
| Keywords | Peptidoglycan | en_US |
| Keywords | Immune proteins | en_US |
| Title | Synthesis of Peptidoglycan Fragments to Probe the Chemical Biology of the Innate Immune System | en_US |
| Type | Thesis | en_US |