Selective targeting of RNA with small molecules: Design and synthesis of ligands for selective binding to RNA bulges and hairpin loops.

摘要

Exploration of the many roles of cellular RNA has begun in earnest only in recent years, and the continuing discovery of new classes and functions of RNA may reveal numerous new opportunities for drug discovery. While methods for targeting proteins and DNA with such small molecules are quite advanced, current approaches to targeting RNA are comparatively rudimentary. The single-stranded nature of RNA presents two avenues for such selective targeting: secondary structure and primary sequence.;Deformations to the A-form helix of RNA are common and predictable. One such deformation, a bulge, occurs when one or more bases of one strand are unpaired. Small molecules inspired by a natural product and a synthetic analogue have been designed, synthesized and assessed to determine their RNA binding properties. These compounds were designed to contain two separate aromatic systems disposed at a particular angle, which permits their binding to RNA bulges. The ligands exhibit low- to mid-micromolar affinities for bulges of various sizes.;Hairpin loops occur in a region of RNA that doubles back on itself, leaving several unpaired bases at the terminus of a duplexed region. Dimers of 2-deoxystreptamine are known to bind to this class of secondary structure. Certain functionalized napthyridines are also known to display the appropriate donor-acceptor relationship to have a selective hydrogen bonding interaction with guanine. An effort was undertaken to combine these two disparate types of binding to enhance the overall selectivity of the ligand. The resulting compounds extended the methodology for binding to hairpin loops, and expanded the available repertoire for the chemistry of naphthyridines.