Biophysics Seminar Series

The Biophysics Virtual Seminar Series presents:

Dr. Gabriele Varani - Department of Chemistry, University of Washington

"Small drug-like molecules targeting RNA with nanomolar affinity and cellular activityon"

Join us on Zoom: https://umich.zoom.us/j/99793210061

ABSTRACT: The ever expanding appreciation of the role of RNA in healthy and disease cellular states has created ever increasing opportunities to redress human disease by targeting RNA with small molecules. However, the chemistry of small molecules targeting RNA remains a challenge. The academic literature has been littered since the mid-1990s with reports of small molecules binding to RNA that, in most cases, did not have the pharmaceutical properties of successful drug candidates and did not bind to RNA potently nor specifically. Screening protein-directed chemical libraries allows the discovery of drug-like molecules that bind to RNA, but success rates are low, typically 1/10,000, and affinity typically in the low to mid-uM range. We have discovered RNA-binding small molecules that obey Lipinski and RO5 rules and bind to RNA potently (low to mid nM) and specifically (discriminate single nucleotide changes). These molecules target RNAs considered 'undruggable' with low nM affinity. Their size (<400 Da), absence of charge, and in vitro pharmacological properties (ADME and in vitro pharmacology) are those of favorable drug candidates. We will illustrate two examples of the application of this chemistry by reporting 10 nM ligands for HIV TAR and 100 nM ligands for pre-miR-21 with specific biochemical and cellular activity against this potent oncogene.