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
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
| Angelbello, Alicia J; Disney, Matthew D (2018) Bleomycin Can Cleave an Oncogenic Noncoding RNA. Chembiochem 19:43-47 |
| Angelbello, Alicia J; Chen, Jonathan L; Childs-Disney, Jessica L et al. (2018) Using Genome Sequence to Enable the Design of Medicines and Chemical Probes. Chem Rev 118:1599-1663 |
| Costales, Matthew G; Matsumoto, Yasumasa; Velagapudi, Sai Pradeep et al. (2018) Small Molecule Targeted Recruitment of a Nuclease to RNA. J Am Chem Soc 140:6741-6744 |
| Haniff, Hafeez S; Graves, Amanda; Disney, Matthew D (2018) Selective Small Molecule Recognition of RNA Base Pairs. ACS Comb Sci 20:482-491 |
| Velagapudi, Sai Pradeep; Luo, Yiling; Tran, Tuan et al. (2017) Defining RNA-Small Molecule Affinity Landscapes Enables Design of a Small Molecule Inhibitor of an Oncogenic Noncoding RNA. ACS Cent Sci 3:205-216 |
| Costales, Matthew G; Haga, Christopher L; Velagapudi, Sai Pradeep et al. (2017) Small Molecule Inhibition of microRNA-210 Reprograms an Oncogenic Hypoxic Circuit. J Am Chem Soc 139:3446-3455 |
| Disney, Matthew D; Angelbello, Alicia J (2016) Rational Design of Small Molecules Targeting Oncogenic Noncoding RNAs from Sequence. Acc Chem Res 49:2698-2704 |
| 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 |
| 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 |
| 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 |
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