# Small Molecules that Activate Cytoprotective Functions of Tyrosyl-tRNA Synthetase

> **NIH NIH P20** · UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA · 2021 · $223,500

## Abstract

ABSTRACT
Aminoacyl-tRNA synthetases (aaRSs) are enzymes that activate L-amino acids for protein synthesis. However,
during evolution, aaRSs progressively accrued ‘moonlighting’ functions that are activated under conditions of
diminished protein synthesis and that enable aaRSs to regulate metabolic homeostasis and modulate signal
transduction pathways. In particular, Tyrosyl-tRNA synthetase (TyrRS) moves into the nucleus under stress
conditions and facilitates DNA repair through poly-ADP-ribose polymerase 1 (PARP1) activation. PARP1, the
central regulator of nicotinamide adenine dinucleotide (NAD+) signaling, senses and responds to DNA damage
and activates DNA repair pathways. Unrepaired or erroneously repaired DNA double strand breaks (DSBs) in
neurons are a major contributing factor in the development of a variety of neurological disorders including
Alzheimer’s disease (AD). In particular, accumulation of amyloid β(Aβ), a hallmark of AD, exacerbates the
accumulation of DSBs in neurons. Remarkably, PARP1 is downregulated in AD and the TyrRS-PARP1
pathway was shown to attenuate Aβ-induced neurotoxicity. Stimulation of this pathway could offer a new
approach to the treatment of AD and other neurodegenerative diseases. We hypothesize that the L-tyrosine
binding pocket of eukaryotic TyrRS can be targeted to design and develop small molecules named TyrRS-
Targeting Compounds (TTCs), which will activate the moonlighting functions of TyrRS that stimulate DNA
repair, and that such molecules will exert neuroprotective activities in AD-relevant models. In the first year of
this project, we have designed and synthesized a series of TTCs on the basis of our work published in Nature,
which demonstrated that the cis-isomer of resveratrol (RSV) binds to TyrRS and acts as an L-tyrosine
antagonist, activating PARP1-dependent signaling cascades. Some of the newly synthesized TTCs have
already shown neuroprotective activity in vitro. Mechanistic analysis indicated that the lead neuroprotective
compound activates AKT and upregulates DNA repair proteins. In the remaining period, we will pursue the
following Specific Aims. Under Aim 1, we will continue structure-based design and synthesis of TyrRS
Targeting Compounds (TTCs) based on the cis-RSV-bound co-crystal structure of TyrRS and demonstrate that
such molecules engage and affect their TyrRS target. Under Aim 2, we will determine the effect of TTCs on
the survival of primary cortical neurons and TyrRS/PARP1-dependent DNA repair and signaling cascades.
Under Aim 3, we will test the in vivo therapeutic potential of TTCs that show neuroprotection in vitro using
5XFAD mouse model of AD. The completion of these Aims will provide proof-of-principle data that would guide
the eventual development of a new class of drugs that targets TyrRS to activate PARP1-dependent DNA repair
in neurons, with potential applicability to AD and other neurodegenerative diseases that originate from
accumulated DNA damage.

## Key facts

- **NIH application ID:** 10221719
- **Project number:** 5P20GM109091-08
- **Recipient organization:** UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
- **Principal Investigator:** Sajish Mathew
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $223,500
- **Award type:** 5
- **Project period:** 2014-07-10 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10221719

## Citation

> US National Institutes of Health, RePORTER application 10221719, Small Molecules that Activate Cytoprotective Functions of Tyrosyl-tRNA Synthetase (5P20GM109091-08). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10221719. Licensed CC0.

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