# Harnessing Small Molecules to Probe the Structure and Function of Regulatory RNAs

> **NIH NIH R35** · DUKE UNIVERSITY · 2022 · $425,320

## Abstract

PROJECT SUMMARY
Despite the recent explosion of interest in RNA targeting, therapeutic potential is presently limited by a lack of
fundamental understanding of how to achieve selective and functional small molecule targeting. The overarching
focus of our research program is to elucidate the key drivers of selectivity in small molecule:RNA recognition and
to apply these principles to facilitate development of RNA-targeted chemical probes and therapeutics that
modulate RNA function. To begin, we identified physicochemical, structural, and spatial properties of biologically
active RNA ligands that are distinct from those of protein-targeted ligands. Synthetic elaboration of RNA binding
scaffolds into a library enriched with these properties has led to improved recognition of disease relevant RNA,
including viral and long noncoding RNA structures. We used pattern recognition protocols to identify RNA
topologies that can be differentially recognized by small molecules and have elaborated this technique to
visualize conformational changes. This combined work has led to remarkable successes such as the targeting
of enterovirus 71 RNA, where our ligand induced a dramatic conformation change that increased binding of a
repressive human protein, decreased viral translation, and inhibited viral replication. Our approach is also
showing preliminary success against SARS-CoV2 regulatory RNA.
Building off these accomplishments, we propose to develop new libraries and screening methods to understand
functional selectivity against a range of more complex tertiary and quaternary structures. Insights into the most
critical driving factors will be revealed through pattern recognition / machine learning analysis as well as through
an ensemble-based QSAR method that will allow rational targeting of any RNA. Key determinants of biological
selectivity will be revealed in high throughput cell-based assays. These discoveries will be further enhanced by
elucidation of the structure-dynamics-function relationships of oncogenic long noncoding RNAs.
Our tools have lowered barriers to the discovery of selective RNA ligands. The proposed work will finally open a
new horizon in RNA-targeting, in which chemical and biological scientists will readily and productively screen for
small molecule probes against a wide range of RNA molecules, including those relevant to human disease. Such
capabilities will allow the therapeutic potential of RNA to be fully exploited and inherently transform our
understanding of molecular biology.

## Key facts

- **NIH application ID:** 10405219
- **Project number:** 2R35GM124785-06
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Amanda E Hargrove
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $425,320
- **Award type:** 2
- **Project period:** 2017-09-15 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10405219

## Citation

> US National Institutes of Health, RePORTER application 10405219, Harnessing Small Molecules to Probe the Structure and Function of Regulatory RNAs (2R35GM124785-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10405219. Licensed CC0.

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