# Building Better Antioxidants: Virtual Screening, Synthesis, and Characterization of Multifunctional Small Molecules Combining Nrf2 Pathway Activation and Direct Antioxidant Activity

> **NIH NIH R15** · TEXAS CHRISTIAN UNIVERSITY · 2022 · $379,063

## Abstract

PROJECT SUMMARY/ABSTRACT
Uncontrolled oxidative stress contributes to the development of neurodegenerative and ocular diseases for
which there are yet to be effective therapeutic interventions. The investigators have developed small
molecules that exhibit significant antioxidant reactivity in biological assays through two mechanisms: direct
reactivity with reactive oxygen species and catalytic activation of the Nrf2 pathway. The investigators will
incorporate virtual screening, rational design, synthetic chemistry, and molecular biology methods to
produce enhanced antioxidant small molecules and understand how the small molecules activate catalytic
antioxidant pathways.
New molecules produced from this project are expected to provide radical scavenging activity, metabolic
stability, and permeability. We propose four mechanisms of achieving improvement in these features
compared to parent molecules. Virtual screening will be used to identify what combination of these
approaches will yield the most promising targets. Following synthesis of these targets, cellular models for
neurodegenerative and ocular disease (e.g. cataracts) will be used to test for protection from oxidative stress.
Molecules showing potent antioxidant activity will then be screened for metabolic stability and blood brain
barrier permeability. Explorations will also be focused on uncovering the mechanism(s) through which our
small molecules protect through catalytic activation of innate antioxidant pathways in biology (Nrf2). Cell
lysates from models exposed to ROS will be evaluated for Nrf2 and its downstream genes including NQO1,
HO-1, SOD, GPX, and Trx, for example. The relationship between Nrf2 and inflammation is also explored.
This approach will identify the path(s) of protection each strategy of antioxidant enhancement provides and
identify lead molecules to be explored further and proceed to future work involving animal toxicology,
clearance, and activity assessment.
Altogether, a comparative approach that uses data from chemical assays and biological studies will allow
the investigators to identify molecules and moieties that provide the characteristics needed to serve as a
therapeutic for neurodegenerative and ocular disorders arising from oxidative stress. This proposal takes a
unique approach to targeting oxidative stress by using computational and synthetic chemistry to combine
different reactive building-blocks into small molecules designed to have activity through targeting
molecular features of neurodegeneration and diseases of the eye in a manner that is greater than the sum of
the individual parts.

## Key facts

- **NIH application ID:** 10360130
- **Project number:** 2R15GM123463-02
- **Recipient organization:** TEXAS CHRISTIAN UNIVERSITY
- **Principal Investigator:** Giridhar Akkaraju
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $379,063
- **Award type:** 2
- **Project period:** 2018-06-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10360130

## Citation

> US National Institutes of Health, RePORTER application 10360130, Building Better Antioxidants: Virtual Screening, Synthesis, and Characterization of Multifunctional Small Molecules Combining Nrf2 Pathway Activation and Direct Antioxidant Activity (2R15GM123463-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10360130. Licensed CC0.

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