Date of Award

Spring 1-1-2018

Document Type

Thesis

Degree Name

Master of Science (MS)

First Advisor

Hubert Yin

Second Advisor

David Walba

Third Advisor

Maciej Walczak

Abstract

Toll-like receptors (TLRs) detect invading viral and bacterial pathogens and play a critical role in the initiation and regulation of the innate immune system. Over-active TLR signaling has been indicated in the disease pathology of numerous crippling inflammatory autoimmune disorders and inhibition of these receptors is of considerable interest for therapeutic intervention. TLR7 and TLR8 are the two TLRs that share the most similarity in both sequence and structure. Despite their similarity, selective inhibition represents a promising therapy for diseases such as systemic lupus erythematosus (lupus) and rheumatoid arthritis (RA). The goal of this master’s thesis is to identify small molecule inhibitors of TLR7 and TLR8 through the use of structure-activity relationship (SAR) studies and the synthesis of a diverse and complex library based around the native ligands of these receptors.

Chapter 1 begins with a brief overview of TLR structure, function, and signaling. Next TLR7 and TLR8 will be discussed including the role they play in lupus and RA as well as the current state of TLR7/8 inhibitors. Chapter 2 discusses the synthesis of TLR8 inhibitors, identified from a cell-based high-throughput screen (HTS). A series of 14 analogs were synthesized with the aim of improving TLR8 inhibition. Chapter 3 focuses on the development of a diverse and complex library based around the native ligands of these receptors. The justification, feasibility, research design, and progress will be discussed. Finally, chapters 4 and 5 are the experimental and characterization of the compounds synthesized in these projects.

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