# Structural Basis for Antiviral Drug Mitochondrial Toxicity

> **NIH NIH R01** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2022 · $391,230

## Abstract

ABSTRACT
Coinfection of HIV and HCV is a major public health threat and requires integrated therapeutic regimens. The
cornerstones of antiretroviral therapy (ART) are nucleoside analogue inhibitors, nucleoside reverse
transcriptase inhibitors (NRTIs) against HIV and ribonucleoside analog inhibitors (RAIs) against HCV. Despite
several success cases, many compounds with similar chemical structures failed during clinical trials due to
drug toxicity. Investigations have revealed that NRTIs' toxicity is mediated by mitochondrial DNA polymerase,
Pol g, and RAIs cross-react with mitochondrial RNA polymerase (hmtRNAP), causing mitochondrial
dysfunction. Mitochondria are vital to cellular activities; they supply energy to the cell, regulate cell cycle and
cell death through apoptosis and participate in innate immunity. Our central hypothesis is that inhibition of
human mitochondrial polymerases is a major cause of antiviral drug toxicity. The long-term goal of our
research is to understand and overcome mitochondrial drug toxicity. We propose to reveal the structural and
molecular mechanism for nucleoside-based antiviral drug mitochondrial toxicity by studying antiviral drug
interactions with both human DNA and RNA polymerases. Our specific aims include 1) to reveal structural
basis for Pol g's two-pronged defense against NRTIs and 2) to provide a mechanism for hmtRNAP mediated
RAIs drug toxicity. The proposed studies will offer a comprehensive view for mitochondrial polymerases
mediated antiviral drug toxicity, and provide insight in design of low-toxic antiviral reagents.

## Key facts

- **NIH application ID:** 10356145
- **Project number:** 5R01AI134611-05
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** Yuhui Yin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $391,230
- **Award type:** 5
- **Project period:** 2018-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10356145

## Citation

> US National Institutes of Health, RePORTER application 10356145, Structural Basis for Antiviral Drug Mitochondrial Toxicity (5R01AI134611-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10356145. Licensed CC0.

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