Expanding the Facets of Multi-Functional Antioxidant Molecules Through Computational Design and Biological Tools

Texas Christian University, Fort Worth TX

Investigators

Linked publications & trials

Abstract

Project Summary Chronic oxidative stress is a challenge to human health, being a major player in chronic and devastating diseases and disorders including but not limited to Alzheimer’s, macular degeneration, kidney disease, Friedreich’s ataxia, cancer, and inflammatory bowel syndrome. Yet, we approach treatment of each disease differently despite a common pathology throughout (oxidative stress). The objective of this proposal is to show that small molecules achieve control of oxidative stress and prevent damage to cells, lipids and other macromolecular structures through multiple, catalytically driven pathways. Broadly, the demonstration that control of oxidative stress is a viable approach to prevent or halt disease would result in improved strategies resulting in more positive patient outcomes long-term. The investigators have developed a class of small molecules that exhibit significant antioxidant reactivity in biological assays through two mechanisms: direct reactivity with reactive oxygen species and catalytic detoxification of those species. The catalytic reactivities observed are multi-fold: (1) Activate the Nrf2 transcription pathway that generates a plethora of antioxidant enzymes, (2) Highly stable metal complexes are mimics of superoxide dismutase and catalase, and (3) (based on preliminary data) anti-ferroptotic. Our goal for this project is to demonstrate that the multifaceted reactivities of these molecules is controllable and predictable. The investigators will incorporate virtual screening, synthetic chemistry, and molecular biology methods to produce enhanced antioxidant small molecules and understand how the small molecules activate catalytic antioxidant reactivities. Specifically, a new virtual screening workflow based on recent advances in computation will be used to identify the most promising targets from a library of >10,000 molecules. Following synthesis of these targets, cellular models for neurodegenerative and ocular diseases will be used to test for protection from oxidative stress. Molecules that show protection will be evaluated for Nrf2 activation by measuring the levels of downstream genes including NQO1 and HO-1 using qPCR and western blot analysis, for example. Biomimetic activity will first be measured in benchtop assays and then transferred to cell models. Lastly, markers for ferroptosis will be evaluated for anti-ferroptotic activity resulting from iron binding. Molecules showing potent antioxidant activity will also be screened for metabolic stability and blood brain barrier permeability. This approach will identify the path(s) of protection, physiochemical properties related to drug-like behavior and, identify lead molecules to be explored further and proceed to future work involving animal toxicology, clearance, and activity assessment.