RNA has essential and diverse biological functions including catalysis, gene regulation, and cellular localization. Aberrant function can lead to diseases such as cancer, cystic fibrosis, and muscular dystrophy. Taken together, RNA is an important therapeutic target for small molecule intervention. The rate at which new RNA targets are being discovered is increasing due to genomic sequencing efforts. In contrast, methods to design or screen ligands for binding to and modulating RNA function are lagging far behind. The most common method employed to identify small molecules that bind RNA is high throughput screening. Unfortunately, the hit rates for RNA targets are much lower than proteins. This is in part due to the lack of understanding about the features in small molecules that pre-dispose them for binding RNA and a lack of understanding about the RNA space that is targetable, significantly hampering developments in the fields of RNA therapeutics and RNA chemical biology. The goal of the proposed work is to develop computational methods to identify druggable RNA targets in genomic sequences and secondary structures and to rationally design small molecule ligands to target them.
The specific aims of the proposal are: (1) Establish a computational approach to identify RNAs that can be targeted with a small molecule. a.) Construct a searchable database of RNA motif-ligand interactions that have been previously identified. The database will be constructed using the open-source MySQL relational engine and will be accessible via a command-line interface and the web;b.) Develop a computer program that searches RNA secondary structures to identify RNA domains that have two or more motifs that bind a ligand in the database;c.) Update the searchable database as new information on small molecules targeting RNA becomes available in the literature. Provide open access to the software via a server on the web. (2) Use these computational tools to search the secondary structures of all human pri- and pre- microRNAs for overlap with the database described in Aim 1. Based on this overlap, ligands will be designed that bind two or more motifs present in a microRNA of interest and will be synthesized using a modular assembly approach in order to enhance target affinity and specificity. (3) Test monomeric and modularly assembled ligands for targeting the microRNA to which they were designed to bind using biochemical techniques. Determine the ligand binding site in the presence and absence of total cellular RNA and ligand potency in vivo using a dual luciferase reporter system. Project Description Page 6

Public Health Relevance

RNA is an important biomolecule that is associated with disease states;however, very few drugs target it. The goal of the proposed research is to compile all known RNA-small molecule interactions and develop computational tools to design ligands that bind to an RNA associated with disease and modulate its function. Public Health Relevance Statement Page 7

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Macromolecular Structure and Function D Study Section (MSFD)
Program Officer
Preusch, Peter C
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Florida
United States
Zip Code
Park, HaJeung; Tran, Tuan; Lee, Jun Hyuck et al. (2016) Controlled dehydration improves the diffraction quality of two RNA crystals. BMC Struct Biol 16:19
Childs-Disney, Jessica L; Disney, Matthew D (2016) Approaches to Validate and Manipulate RNA Targets with Small Molecules in Cells. Annu Rev Pharmacol Toxicol 56:123-40
Velagapudi, Sai Pradeep; Cameron, Michael D; Haga, Christopher L et al. (2016) Design of a small molecule against an oncogenic noncoding RNA. Proc Natl Acad Sci U S A 113:5898-903
Liu, Biao; Childs-Disney, Jessica L; Znosko, Brent M et al. (2016) Analysis of secondary structural elements in human microRNA hairpin precursors. BMC Bioinformatics 17:112
Disney, Matthew D; Angelbello, Alicia J (2016) Rational Design of Small Molecules Targeting Oncogenic Noncoding RNAs from Sequence. Acc Chem Res 49:2698-2704
Disney, Matthew D; Winkelsas, Audrey M; Velagapudi, Sai Pradeep et al. (2016) Inforna 2.0: A Platform for the Sequence-Based Design of Small Molecules Targeting Structured RNAs. ACS Chem Biol 11:1720-8
Childs-Disney, Jessica L; Disney, Matthew D (2016) Small Molecule Targeting of a MicroRNA Associated with Hepatocellular Carcinoma. ACS Chem Biol 11:375-80
Yang, Wang-Yong; Wilson, Henry D; Velagapudi, Sai Pradeep et al. (2015) Inhibition of Non-ATG Translational Events in Cells via Covalent Small Molecules Targeting RNA. J Am Chem Soc 137:5336-45
Bernat, Viachaslau; Disney, Matthew D (2015) RNA Structures as Mediators of Neurological Diseases and as Drug Targets. Neuron 87:28-46
Haga, Christopher L; Velagapudi, Sai Pradeep; Strivelli, Jacqueline R et al. (2015) Small Molecule Inhibition of miR-544 Biogenesis Disrupts Adaptive Responses to Hypoxia by Modulating ATM-mTOR Signaling. ACS Chem Biol 10:2267-76

Showing the most recent 10 out of 19 publications