We seek to create a rapid and generic approach for discovery of small molecule ligands that bind RNA specifically and elicit precise and useful biological effects. The difficulty of this challenge is exemplified by the observation that the number of highly effective small molecule ligands that bind RNA that were developed de novo by human ingenuity over the past 30 years is miniscule, perhaps two or three molecules at most. The overarching vision of this proposal is to make the process of ligand discovery both straightforward and generically applicable to arbitrary RNA targets. This goal will be pursued by leveraging the SHAPE (selective 2'-hydroxyl acylation analyzed by primer extension) chemical probing approach - invented, mechanistically validated, and broadly applied by the project laboratory - into a high-throughput and high- content ligand discovery technology for RNA. Nucleotide-resolution screening information for large RNA targets will be interpreted using innovative, and fully automated, analysis algorithms that leverage the exceptionally information-rich output of SHAPE probing to make possible rapid target identification by non-expert users. By the end of the funding period, we envision that small molecule targeting of RNA using fragment-based libraries will be no more difficult, and may even prove more straightforward than, conventional targeting of proteins. Specifically, we expect to establish estimates for the broad-based drugability of RNA, to characterize the properties of selective and useful small molecule fragments for targeting RNA, and to identify multiple small molecule compounds useful as structure-probing tools and as leads for developing highly potent antiviral therapeutics.

Public Health Relevance

This unconventional and innovative proposal is focused on inventing new ways to create drugs that work by binding to RNA. Because many serious human illnesses involve RNA components - including the RNA genomes of viruses like HIV and HCV, the specialized RNA recognition elements in cancer-causing genes, and the pathogenic RNA structures that cause currently incurable hereditary tri-nucleotide expansion diseases - the potential impact of this project is exceptionally wide-ranging.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM098662-04
Application #
8727061
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Preusch, Peter
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Warner, Katherine Deigan; Homan, Philip; Weeks, Kevin M et al. (2014) Validating fragment-based drug discovery for biological RNAs: lead fragments bind and remodel the TPP riboswitch specifically. Chem Biol 21:591-5