Year of Award
2026
Document Type
Dissertation
Degree Type
Doctor of Philosophy (PhD)
Degree Name
Chemistry (Organic Option)
Other Degree Name/Area of Focus
Medicinal Chemistry
Department or School/College
Department of Chemistry and Biochemistry
Committee Chair
Orion Berryman
Commitee Members
Kendal Ryter, Nigel Priestley, Christopher Palmer, Andrea Stierle
Keywords
Medicinal Chemistry, Structure-Activity Relationship Studies
Abstract
Bacterial and viral infections often result in lower respiratory infections, which is the fourth leading cause of death worldwide. Given the major health threat imposed by these pathogens, therapeutic development for protection and reduced symptom severity is critical. Historically, deactivated pathogens have been implemented for vaccine use and show sufficient protection. However, this strategy falls short when the pathogen rapidly evolves to evade immunity. Alternative approaches, such as the use of small molecules to stimulate the innate immune system, is a growing field in organic and medicinal chemistry to combat current vaccine limitations. This dissertation implements small molecule immunostimulant discovery for two distinct immunological targets: The macrophage inducible C-type lectin receptor (Mincle) receptor and the Interleukin-1 (IL-1) pathway.
The use of small molecules to stimulate the immune system is not a novel concept. Currently, there are five major adjuvant systems that are FDA-approved that broadly stimulate the immune system or activate through Toll-like Receptors (TLRs). Although these adjuvants can skew a TH1 response, no approved adjuvant produces a TH17 response. Combination of a TH1/TH17 immune response is essential for broad pathogen protection. Mincle signaling can lead to a TH1/Th17 response, therefore Mincle ligand development targets a critically unmet need. Additionally, targeting a downstream cytokine pathway could limit unwanted reactogenicity while inducing the production of essential immunological cytokines such as IL-1β and IL-6. This dissertation addresses two critical knowledge gaps: Mincle ligand investigation and discovery of novel IL-1 pathway immunostimulants.
Chapter 1 provides a broad-spectrum introduction to innate immune signaling pathways and the current therapeutic research underway. Chapter 2 focuses on elucidating key requirements of Mincle activation via trehalose-derived analogs. Specifically, the sugar-lipid moiety linker and the lipid moiety carbon chain length were investigated and evaluated biologically. The results discussed demonstrate the high sensitivity of Mincle activation via small molecules. Additionally, this foundational work informed future development of new trehalose-derived analogs. Chapter 3 centers on the discovery of novel nicotinonitrile analogs that activate via the IL-1 pathway. This series is first in class, demonstrating IL-1 pathway activation rather than suppression. Extensive structure-activity relationship studies were performed to evaluate essential hydrophobic and electronic requirements required to illicit biological response. The results identified lead analogs with promising biological activity, that will be further studied by mechanism of action and refined SAR studies. Chapter 4 is a conclusion, largely highlighting key results from each chapter and discussing future directions.
Recommended Citation
Kelly, Allison Denise, "SMALL-MOLECULE MODULATION OF INNATE IMMUNE SIGNALING: SYNTHESIS AND SAR STUDIES OF DISTINCT MINCLE AND IL-1 PATHWAY IMMUNOSTIMULANTS" (2026). Graduate Student Theses, Dissertations, & Professional Papers. 12702.
https://scholarworks.umt.edu/etd/12702
© Copyright 2026 Allison Denise Kelly