Author ORCID Identifier

0000-0003-0695-3155

Defense Date

2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmacy - Dean's Office

First Advisor

Dr. Shijun Zhang

Abstract

Inflammasomes are intracellular multimeric protein complexes that regulate inflammation by controlling the maturation of cytokines, interleukin-1β (IL-1β) and interleukin-18 (IL-18). Additionally, activation of these inflammasome complexes has been implicated in an inflammatory form of death known as proptosis. Of the known inflammasomes, the NOD-like receptor family pyrin domain containing 3 (NLPP3) inflammasome, is the most elucidated. Under physiological conditions, NLRP3-mediated inflammation promotes healing and the elimination of cellular debris and pathogens. However, the dysregulation of IL-1β, IL-18 and pyroptosis are instrumental in the development of multiple pathologies. Furthermore, studies suggest that the NLRP3 inflammasome mediates detrimental neuroinflammation and contributes significantly to the development of several neurodegenerative diseases. This includes Alzheimer’s disease, multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis. Novel NLRP3 inflammasome inhibitors (NLRP3Is) are needed as pharmacological tools to complement ongoing molecular and genetic studies to aid in defining the roles of NLRP3 in neurological diseases. Development of such inhibitors also has significant translational potential. In order to develop novel small molecule inhibitors of the NLRP3 inflammasome, we conducted an in-depth structure-activity-relationship study of a known NLRP3 inhibitor. Two new lead compounds, 54 and 64, were identified. These compounds were potent and selective NLRP3 inhibitors in both in BMDMs and J774A.1 cell-lines. Importantly, a study utilizing mice challenged with LPS demonstrated that both of these compounds have in vivo activity. Collectively, these results strongly encourage further development of new analogs based on this promising chemical scaffold.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

5-10-2018

Available for download on Wednesday, May 10, 2023

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