Toward the Discovery of Small Molecules Affecting RNA Function

Abstract

The Human Genome Project revealed that many noncoding RNAs (ncRNA) were transcribed from the genome. In the case of Homo sapiens, ncRNA comprised 43% of the entire genome, whereas genes transcribed and translated were only 2% of the genome. Furthermore, small interfering RNA (siRNA) and microRNA, which are ncRNA of shorter length, were discovered to play important roles in regulating and maintaining the function of living organisms. These functional RNAs become attractive therapeutic agents and also targets for small organic molecules. Our group has focused attention on molecular technology that regulates the function of DNA and RNA by small organic molecules. A breakthrough on the molecular technologies regulating RNA function was the discovery of the riboswitch, which is a genetic switch for ON and OFF of gene expression by alternating secondary structure of the 5′-untranslated region (UTR) of messenger RNA (mRNA) with the binding of small organic molecules such as adenine and guanine. This discovery clearly showed that, in addition to proteins, the ncRNA is the distinct target of small organic molecules to regulate gene expression. However, neither the research tools for the discovery of small organic molecules binding to specific RNA targets nor the design principle for those RNA-binding molecules was fully developed. We here describe our approach for the research tools for the discovery of RNA-binding molecules from a large chemical library and the attempt of molecule binding between hairpin loops of DNA and RNA.