# Modulating gene expression by RNA-targeting chimeras

> **NIH NIH R35** · UNIVERSITY OF KANSAS LAWRENCE · 2022 · $382,500

## Abstract

PROJECT SUMMARY
 RNA-binding small molecules have the potential to modulate the expression of genes whose protein
products were previously considered “undruggable.” Risdiplam, targeting a precursor mRNA, was recently
approved for the treatment of spinal muscular atrophy (SMA) and demonstrates the specificity and safety
attainable by this approach. Although a variety of small-molecule scaffolds have been uncovered as RNA-binding
ligands, their use is hampered by (1) lack of specificity and (2) unpredictable function. We propose a research
program that will provide RNA-targeting chemical probes that will avoid these drawbacks. Inspired by Proteolysis
Targeting Chimera (PROTAC) technology, we are designing chimeric molecules that will target RNA specifically
and carry (deliver) the ability to induce RNA degradation or inhibit RNA translation, in a highly predictable manner.
 Our initial efforts towards an RNA-targeting chimera platform use a newly discovered RNA-binding
coumarin derivative as a model and fine-tune its preferential binding properties through chemical modification.
Through structural optimization, which includes using a “bidentate” RNA ligand strategy, we expect to achieve
RNA-binding selectivity equal to or greater than that of oligonucleotides. At the same time, we propose to develop
and optimize three novel effectors to precisely degrade RNA targets or inhibit the target RNA translation. These
new effectors have shown promising results in inhibiting Zika virus (an RNA virus) gene expression. Ultimately,
our proposed work will generate a top-down method for designing selective gene expression inhibitors that are
independent of the gene's protein product.
 The long-term goal of our lab is to build a medicinal chemistry platform for making gene-specific and
patient-specific therapies using RNA-binding small molecules. In this process, we will not only generate various
tool compounds for studying important disease-modifying genes, but also combine computational and
experimental technologies to understand the detailed mechanism of RNA-small molecule recognition.

## Key facts

- **NIH application ID:** 10500813
- **Project number:** 1R35GM147498-01
- **Recipient organization:** UNIVERSITY OF KANSAS LAWRENCE
- **Principal Investigator:** Jingxin Wang
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $382,500
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10500813

## Citation

> US National Institutes of Health, RePORTER application 10500813, Modulating gene expression by RNA-targeting chimeras (1R35GM147498-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10500813. Licensed CC0.

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