Related Experiment Video
Updated: May 9, 2026
11:34
Exploring Sequence Space to Identify Binding Sites for Regulatory RNA-Binding Proteins
Published on: August 9, 2019
An RNA-Focused DNA-Encoded Library Platform for Discovering Ligands of Pathogenic r(G4C2)exp RNA.
Xueyi Yang1,2, Amirhossein Taghavi2, Yoshihiro Akahori2
1Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States.
ACS Chemical Biology
|May 8, 2026
Summary
Researchers developed a DNA-encoded library (DEL) to find small molecules targeting toxic RNA repeats. This approach successfully identified and optimized drug leads for diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Computational Chemistry
Background:
- Disease-associated RNAs are emerging as key therapeutic targets for small-molecule drugs.
- DNA-encoded libraries (DELs) are effective for discovering protein ligands and are now being explored for RNA-binding small molecules.
Purpose of the Study:
- To develop a novel DEL platform enriched in RNA-binding scaffolds for identifying small-molecule ligands targeting toxic RNA repeat expansions.
- To identify and optimize ligands for the r(G4C2)exp RNA, implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
Main Methods:
- Construction of a diverse, solid-phase DEL enriched in privileged RNA-binding scaffolds.
- Application of DEL selection to identify ligands for the r(G4C2)exp RNA.
- Analysis of DEL selection outcomes using large-scale molecular docking, physicochemical analysis, and structure-activity relationship (SAR) studies.
- Rational design and optimization of lead compounds based on computational and experimental data.
Main Results:
- Successful identification of small-molecule ligands for the r(G4C2)exp RNA using the DEL platform.
- Observed correlations between molecular docking predictions and experimental enrichment trends, validating the computational approach.
- Optimization of lead compounds resulted in analogues with improved binding affinity and bioactivity.
Conclusions:
- The combination of DEL technology with computational approaches provides a powerful and adaptable platform for RNA-targeted small-molecule discovery.
- This strategy is effective for identifying and optimizing ligands against disease-associated RNA targets, offering potential therapeutic avenues for neurodegenerative diseases.
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