Date of Award

Spring 1-1-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Hang Yin

Second Advisor

Wei Zhang

Third Advisor

Xuedong Liu

Fourth Advisor

Corrie Detweiler

Fifth Advisor

Linda Watkins

Abstract

Immune system plays a critical role in defense against various virus and bacteria, and it’s composed of innate immune system and adaptive immune system. Innate immune system is vital for immune response because of its prompt responses to a variety of pathogens as well as its selectivity for targeting only pathogens not the host. The innate immune system achieves this by using receptors to recognize certain molecular patterns that are common in many pathogens but are not present in the host. These receptors are known as pattern recognition receptors (PRR), they can recognize pathogen-associated molecular pattern (PAMP) as well as damage-associated molecular pattern (DAMP).

Among pattern recognition receptors, Toll-like receptors (TLRs) are the most well studied ones. Toll-like receptors (TLRs) play a key role in the innate immune system by recognizing structurally conserved PAMP and DAMP. The goal of this doctoral dissertation research is to design, synthesis and evaluate TLR8 antagonists.

Chapter 1 focus on introduction of immune system including innate immune system and adaptive immune system. Pattern recognition receptors are then introduced, and Toll-like receptors are specially focused on.

Chapter 2 describes the design and development of TLR8 antagonist utilizing structure-based rational design. And Structure–Activity Relationship (SAR) study of TLR8 antagonists is introduced in chapter 3.

Chapter 4 describes the mechanism of TLR8 inhibition induced by CU-CPT antagonists. Chapter 5 introduces biological validation of CU-CPT antagonists, showing high potency and selectivity of these compounds, which indicates the therapeutic potential of CU-CPT derivatives. Methods and supporting information are listed in Chapter 6 and 7.

Share

COinS