Date of Award

Spring 4-18-2024

Embargo Period

4-25-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Drug Discovery and Biomedical Sciences

College

College of Graduate Studies

Additional College

College of Pharmacy

First Advisor

Patrick Woster

Second Advisor

Yuri Peterson

Abstract

The major intracellular polyamines spermine and spermidine are abundant endogenous compounds that are essential for cellular growth and development. Dysregulation of polyamine metabolism has been implicated as a key mechanism of injury across multiple forms of clinically challenging pathologies. Of the enzymes within the polyamine pathway, the catabolic enzyme spermine oxidase (SMOX) is of particular interest as it is subject to induction in response to infection, neuronal excitotoxicity, ischemia, and oxidative stress. In addition to the loss of radical scavenging capabilities associated with spermine depletion, catabolism of spermine by SMOX results in the production of toxic byproducts, including H2O2 and acrolein, a highly toxic aldehyde with the ability to form adducts with DNA and inactivate vital cellular proteins. Catabolism of spermine by SMOX has been identified as the most significant endogenous source of acrolein, highlighting the importance of this enzyme in acrolein-mediated cellular damage. Despite extensive evidence implicating SMOX as a key enzyme contributing to secondary injury associated with multiple pathologic states, the lack of potent and selective inhibitors has significantly impeded investigation of SMOX as a therapeutic target. In this study, we used a virtual and physical screening approach to identify and characterize a series of compounds with inhibitory activity against SMOX. Hit compounds underwent enzymatic characterization for potency, selectivity, and mechanism of inhibition. In addition, select compounds were assessed for the ability to alter cellular response. In this work we describe the identification of two unique structural scaffolds demonstrating selective inhibition of SMOX, representing the most potent competitive SMOX inhibitors reported to date. The majority of structural derivates that were characterized in this work maintained inhibitory activity for SMOX, despite minor structural variations, indicating the discovery of a fundamentally novel pharmacophore with the ability to tolerate further chemical modification in the development of targeted therapies suitable for in vivo studies and ultimately, to aid in the development of compounds suitable for clinical evaluation.

Rights

Copyright is held by the author. All rights reserved.

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