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

> **NIH NIH R35** · DUKE UNIVERSITY · 2020 · $380,571

## Abstract

Project Summary
The long-term goal of the PI is to develop highly specific, RNA-targeted, small molecule ligands to probe the
dynamic structure, fundamental biology, and therapeutic potential of long noncoding RNAs (lncRNAs). Select
lncRNAs have been found to play critical roles in cancer progression, including lncRNA HOTAIR, which is
implicated in metastatic breast cancer, and lncRNA MALAT-1, which is over-expressed in several cancers,
including non-small cell lung cancer. Despite the proposed therapeutic potential of lncRNAs, adequate small
molecule targeting strategies have yet to be realized. This slow progress is due in part to the nature of RNA as
a dynamic structure with limited chemical functionality but also to a gap in knowledge with respect to guiding
principles and methods for small molecule:RNA interactions. Our central hypothesis is that the parallel
discovery of small molecule chemical space and RNA topological space privileged for differentiation will yield
fundamental insights into small molecule:RNA recognition that can be applied to the rapid development of
ligands with high affinity and specificity for a wide range of RNA targets. In prior work, the PI has identified
common chemical properties of biologically active RNA ligands, elaborated RNA binding scaffolds for improved
recognition of small RNA targets, revealed RNA secondary structures that can be differentially recognized by
small molecules, and computationally identified “hot spots” for targeting lncRNA HOTAIR. In the proposed
work, we will simultaneously pursue two independent but complementary lines of fundamental investigation
and apply the developed guiding principles and technologies to two critical lncRNA targets. In Area 1, we will
use cheminformatic analysis, organic synthesis, and rapid screening methods to identify small molecule
properties biased toward specific RNA recognition. In Area 2, we will use pattern recognition protocols to
identify RNA structures that are readily differentiated by small molecules. In Area 3, we will combine our RNA-
biased libraries and optimized screening assays to identify the first inhibitors of lncRNA tertiary structure,
particularly the 3'-triple helix of MALAT1. In Area 4, we will use a wide range of computational and
experimental tools to identify small molecules that inhibit lncRNA:protein interactions, viz. HOTAIR and its
protein binding partner, PRC2. The rationale for this research is that our novel RNA-specific libraries and
technologies will enable new investigations of RNA structure and function and serve as a rich platform for
future development of RNA targeted therapeutics. In summary, our work will (i) produce the first widely
available RNA-biased molecular library with demonstrated affinity and specificity for RNA targets; (ii) develop a
range of computational, synthetic, and screening tools to enhance RNA ligand identification; and (iii) yield first-
in-class technologies to develop small molecule ligands for lnc...

## Key facts

- **NIH application ID:** 10001564
- **Project number:** 5R35GM124785-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Amanda E Hargrove
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $380,571
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001564

## Citation

> US National Institutes of Health, RePORTER application 10001564, Harnessing Small Molecules to Probe the Structure and Function of Long Noncoding RNAs (5R35GM124785-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10001564. Licensed CC0.

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