Date of Award
Doctor of Philosophy (PhD)
The innate immune system protects us from incessant attacks by microorganisms. However, immunity is a double-edged sword, and inflammation must be carefully regulated. Chemical biology offers a means to maintain healthy homeostasis by influencing the immune response. We have used small molecule and peptide chemistries to exploit Toll-like receptor, caspase, and antimicrobial peptide signaling for therapeutic purposes. These compounds may find applications treating sepsis and autoimmune disease, and can influence the design of next-generation antibiotics and vaccines.
Toll-like receptors are pattern recognition receptors that sense bacteria and viruses, and then induce inflammation to stave off infection. We have designed saccharin-derived small molecules capable of reducing inflammation by inhibiting JAK/STAT1 signaling. We have also explored Toll-like receptor specificity by designing TLR8-specific imidazole-derivatives that are promising immune-responsive vaccine adjuvants.
Caspases are proteases that control inflammation and cell death. Much is still unknown about the role of caspases as innate immune receptors, particularly lipopolysaccharide-sensing caspase-4. We have performed two small molecule screens to identify caspase-4 inhibitors for use as both therapeutics and signaling probes. From this, we have discovered a new role for non-steroidal anti-inflammatory drugs as multi-caspase inhibitors, which may shape patient applications of these essential drugs. We have also identified novel caspase-4 specific small molecules for sepsis treatment.
Antimicrobial peptides are small, amphipathic peptides able to both disrupt bacterial membranes and influence inflammation. We have designed a series of peptidomimetics able to mimic the properties of host-defense peptides. These peptidomimetics are active against a wide array of Gram-positive and Gram-negative pathogens, and reduce the inflammatory response. In an era of prevalent antibiotic resistance, peptidomimetics offer a path for the design of new antibiotics.
Boville, Christina Elizabeth, "Characterization of Chemical Probes for Therapeutic Intervention of Innate Immune Signaling" (2017). Chemistry & Biochemistry Graduate Theses & Dissertations. 204.