Design and Implementation of Synthetic RNA Binders for the Inhibition of miR-21 Biogenesis

Targeting RNAs using small molecules is an emerging field of medicinal chemistry and holds promise for the discovery of efficient tools for chemical biology. MicroRNAs are particularly interesting targets since they are involved in a number of pathologies such as cancers. Indeed, overexpressed microRNAs in cancer are oncogenic and various series of inhibitors of microRNAs biogenesis have been developed in recent years. Here, we describe the structure-based design of new efficient inhibitors of microRNA-21. Starting from a previously identified hit, we performed biochemical studies and molecular docking to design a new series of optimized conjugates of neomycin aminoglycoside with artificial nucleobases and amino acids. Investigation about the mode of action and the site of the interaction of the newly synthesized compounds allowed for the description of structure-activity relationships and the identification of the most important parameters for miR-21 inhibition.