Identification of Nucleic Acid Binding Small Molecules

Division Of Basic Sciences - Nci

Investigators

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Abstract

The goal of this project is to identify and characterize small molecules that target RNA and DNA. Recent estimates indicate that some 85% of the human genome is transcribed into RNA, but just 3% of these transcripts code for protein sequences. Further, just ~15% of proteins are "druggable" by modern medicinal chemistry, while a far greater proportion of gene products have been implicated in human disease. Taken together, these observations indicate that the ability to target DNA, noncoding RNA, or the mRNA of undruggable proteins with small molecules would be a transformative advance in the development of novel therapeutics for diseases that have no cure, including many cancers. We have focused on key questions in this field such as (1) How can we identify potent, selective, biologically active RNA/DNA-binding small molecules? (2) What type of RNA/DNA makes a suitable target for small molecules? (3) What is the structural basis for small molecule recognition of RNA/DNA? And (4) What technologies are needed to better understand, develop, and characterize small molecules that bind to RNA/DNA? Our work provides fundamental discoveries that help understand how to target nucleic acids with small molecules using chemical, biochemical, structural, machine learning, and chemical biology techniques.