Development of Small Molecules Targeting Disease Associated RNAs

For decades, it was thought that RNA mainly served either as the template, in the form of mRNA, or as an adaptor or a structural component during protein synthesis, provided by tRNAs and ribosomal RNAs. The discovery of catalytic RNAs and a multitude of non-coding RNA (ncRNA) species, lead to the recognition that RNA is a highly versatile molecule that is responsible for numerous regulatory functions in cells. Moreover, about 70% of the human genome is transcribed into RNAs, whereas only 1.5% of the genome encodes proteins and only 30% of these are “druggable” targets. To date, approved drugs interact therapeutically with less than 700 of these proteins. For these reasons, RNA represents an attractive alternative therapeutic target. One way to target RNA is via small molecules capable of recognizing and binding RNA-3D structures. We have developed several approaches and compounds capable of alleviating disease-associated phenotypes related to a dysregulated or mutated RNA. Notably, we designed novel small molecules capable of inhibiting oncogenic microRNAs or degrading mutated RNA in genetic diseases. By exploiting evolutionary principles at the earliest stages of drug discovery, it is possible to identify novel, high affinity, and selective target RNA ligand interactions and predict engagements in cells that short-circuit disease pathways in preclinical disease models.