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

Award Number: R15GM123463
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2018
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $406,882 )
2025	2025	TEXAS CHRISTIAN UNIVERSITY	3101 BELLAIRE DRIVE NORTH	FORT WORTH	TX	76129	TARRANT	USA	Biomedical Research and Research Training	002	3	7/23/2025	COMPETING CONTINUATION	$406,882
2025	2022	TEXAS CHRISTIAN UNIVERSITY	3101 BELLAIRE DRIVE NORTH	FORT WORTH	TX	76129	TARRANT	USA	Biomedical Research and Research Training	000	2	6/9/2025	COMPETING CONTINUATION	$0
2025	2022	TEXAS CHRISTIAN UNIVERSITY	3101 BELLAIRE DRIVE NORTH	FORT WORTH	TX	76129	TARRANT	USA	Biomedical Research and Research Training	001	2	7/21/2025	COMPETING CONTINUATION	$0
														Subtotal = $406,882

Issue Date FY: 2022 ( Subtotal = $379,063 )
2022	2022	TEXAS CHRISTIAN UNIVERSITY INC	2800 S UNIVERSITY DR	FORT WORTH	TX	76129	TARRANT	USA	Biomedical Research and Research Training	001	2	1/25/2022	COMPETING CONTINUATION	$379,063
2022	2022	TEXAS CHRISTIAN UNIVERSITY	3101 BELLAIRE DRIVE NORTH	FORT WORTH	TX	76129	TARRANT	USA	Biomedical Research and Research Training	003	2	8/24/2022	COMPETING CONTINUATION	$8,713
2022	2018	TEXAS CHRISTIAN UNIVERSITY	3101 BELLAIRE DRIVE NORTH	FORT WORTH	TX	76129	TARRANT	USA	Biomedical Research and Research Training	002	1	8/24/2022	NEW	-$8,713
2022	2018	TEXAS CHRISTIAN UNIVERSITY INC	2800 S UNIVERSITY DR	FORT WORTH	TX	76129	TARRANT	USA	Biomedical Research and Research Training	000	1	1/17/2022	NEW	$0
														Subtotal = $379,063

Issue Date FY: 2018 ( Subtotal = $378,914 )
2018	2018	TEXAS CHRISTIAN UNIVERSITY INC	2800 S UNIVERSITY DR	FORT WORTH	TX	76129	TARRANT	USA	Biomedical Research and Research Training	000	1	4/16/2018	NEW	$378,914
														Subtotal = $378,914

Grand Total All Awards = $1,164,859

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

Award Number: R15GM123463

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2018

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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