A Library Approach to the Discovery of Small Molecules That Recognize RNA: Use of a 1,3-Hydroxyamine Motif as Core

Abstract

A library of compounds based upon an aminoglucopyranoside core has been developed and screened for binding to RNA and specifically to 16S ribosomal RNA. The title molecules simplify the complexity of naturally occurring aminoglycoside antibiotics by embodying a putative recognition motif found within these structures, namely, a 1,3-hydroxyamine. The core pyranoside bearing the hydroxyamine motif was structurally varied at two points through a combinatorial approach utilizing acylation and reductive amination protocols. The aminoglycoside mimetics were screened in an automated assay based upon surface plasmon resonance (SPR), and some were found effective at binding a 27-nucleotide model (AS-wt) of A-site 16S RNA as well as a drug-resistant mutant RNA in the micromolar range.