# Novel screening platform for O-GlcNAc transferase substrate-specific inhibitors to combat aging-related diseases

> **NIH NIH R36** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $71,875

## Abstract

Project Summary
The O-linked β-N-acetylglucosamine (O-GlcNAc) is an essential post-translational modification
found in thousands of proteins involved in a broad range of important biological processes,
including epigenetics, metabolism, and protein degradation. The O-GlcNAc modification is
dynamically added and removed by a single pair of human enzymes, O-GlcNAc transferase
(OGT) and O-GlcNAcase (OGA), respectively. Dysregulation of O-GlcNAcylation has been
detected in many aging-related diseases including cancer, diabetes, Alzheimer’s and
Huntington’s disease. To date, several effective active-site inhibitors have been reported for OGT
and OGA, but they are likely to induce undesired side effects as these essential enzymes regulate
O-GlcNAc dynamics on thousands of protein substrates. Currently, there is no report on
substrate-specific inhibitors of OGT or OGA, largely due to the lack of suitable assays. Here, I
propose to develop a novel high-throughput screening assay for identifying small molecules that
can specifically bind to different regions of OGT and modulate O-GlcNAcylation of a particular
protein of interest without perturbing the global O-GlcNAc level in cells. From the proposed screen
and the following in vitro and cellular characterization and optimization processes, I expect to
identify several compounds as the first generation of substrate-specific inhibitor candidates of
OGT that can modulate O-GlcNAcylation on particular proteins related to aging diseases. This
new assay platform can be potentially adapted for other protein substrates and facilitate the
therapeutic development to combat aging disorders.

## Key facts

- **NIH application ID:** 10475192
- **Project number:** 5R36AG073801-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Arielis Estevez Davila
- **Activity code:** R36 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $71,875
- **Award type:** 5
- **Project period:** 2021-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10475192

## Citation

> US National Institutes of Health, RePORTER application 10475192, Novel screening platform for O-GlcNAc transferase substrate-specific inhibitors to combat aging-related diseases (5R36AG073801-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10475192. Licensed CC0.

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