Rational Drug Design and High-Throughput Techniques for RNA Targets

Abstract

RNA molecules are the only known molecules which possess the double property of being depository of genetic information, like DNA, and of displaying catalytic activities, like protein enzymes. RNA molecules intervene in all steps of gene expression and in many other biological activities. Like proteins, RNAs achieve those biological functions by adopting intricate three-dimensional folds and architectures. Further, as in protein sequences, RNA sequences contain signatures specific for threedimensional motifs which participate in recognition and binding. In regulatory pathways, RNA molecules exist in equilibria between transient structures differentially stabilized by effectors such as proteins or cofactors. Therefore, RNA molecules display their potential as drug targets on different levels, namely in three-dimensional folds, in structural equilibria and in RNA-protein interfaces. Several examples will be described together with the already available techniques for combinatorial synthesis and high-throughput screening of potential drug and target RNA molecules.

A Homogenous Assay for Micro RNA Maturation

“…Although RNAs contain appropriate target structures for the binding of small molecules, [5] a rational design of selective RNA ligands is extremely difficult. [6] Herein we present for the first time a homogenous, fluorescence-based Dicer assay that allows easy screening of libraries of potential pre-miRNA ligands and therefore potential inhibitors of miRNA maturation.…”

Functional Nucleic Acids in High Throughput Screening and Drug Discovery

“…Expanding knowledge of several new key biological roles played by RNA molecules, especially in the gene expression processes has fueled the growing interest in exploring RNA as disease intervention targets [67][68][69]. Assays similar to those used for protein targets have been implemented in search for compounds that interfere with the functions of therapeutically relevant RNA targets.…”

Chemical and functional diversity of small molecule ligands for RNA

“…After the seminal discovery that aminoglycosides recognize directly the 16S RNA of the small ribosomal subunit, 12-14 the paradigm of RNA as a target for small molecule ligands has been firmly established. 10,15,24,28,29 In vitro selection of RNA aptamers for a chemically diverse variety of ligands has since demonstrated the versatility of RNA molecular recognition. 16 These findings, along with the postulated key role of RNA as an enzymatically active species during a prebiotic RNA world, [91][92][93] have fostered the expectation that small molecule-RNA interactions may be more widespread in the regulation of biological RNA functions.…”