Small molecules targeting viral RNA

Abstract

Highly conserved noncoding RNA (ncRNA) elements in viral genomes and transcripts offer new opportunities to expand the repertoire of drug targets for the development of antiinfective therapy. Ligands binding to ncRNA architectures are able to affect interactions, structural stability or conformational changes and thereby block processes essential for viral replication. Proof of concept for targeting functional RNA by small molecule inhibitors has been demonstrated for multiple viruses with RNA genomes. Strategies to identify antiviral compounds as inhibitors of ncRNA are increasingly emphasizing consideration of drug-like properties of candidate molecules emerging from screening and ligand design. Recent efforts of antiviral lead discovery for RNA targets have provided drug-like small molecules that inhibit viral replication and include inhibitors of human immunodeficiency virus (HIV), hepatitis C virus (HCV), severe respiratory syndrome coronavirus (SARS CoV), and influenza A virus. While target selectivity remains a challenge for the discovery of useful RNA-binding compounds, a better understanding is emerging of properties that define RNA targets amenable for inhibition by small molecule ligands. Insight from successful approaches of targeting viral ncRNA in HIV, HCV, SARS CoV, and influenza A will provide a basis for the future exploration of RNA targets for therapeutic intervention in other viral pathogens which create urgent, unmet medical needs. Viruses for which targeting ncRNA components in the genome or transcripts may be promising include insect-borne flaviviruses (Dengue, Zika, and West Nile) and filoviruses (Ebola and Marburg). WIREs RNA 2016, 7:726-743. doi: 10.1002/wrna.1373 For further resources related to this article, please visit the WIREs website.

Translation initiation by the hepatitis C virus IRES requires eIF1A and ribosomal complex remodeling

“…As these IRESs are found in medically and economically important pathogens, they raise possibilities as drug targets (Davis and Seth, 2010; Dibrov et al, 2012; Hermann, 2016) and are useful tools for exploring both IRES function and fundamental principles of translation initiation, so it is important that we fully understand how they work. Therefore, we re-examined the mechanism used by the HCV IRES with approaches designed to complement previous biochemical and structural studies.…”

Discovery of Key Physicochemical, Structural, and Spatial Properties of RNA‐Targeted Bioactive Ligands

“…[7a, 8] In studies targeting r(CUG)-repeat sequences in 2015, Disney et al tested a drug-like, RNA-biased library of bis-benzimidazoles and similar core structures and found that bioactive molecules had statistically significant differences in topological polar surface area (tPSA) as well as hydrogen bond acceptors (HBA) and donors (HBD). [9] Inspired by this previous work and the recent surge in discoveries of biologically active RNA-targeting ligands, [10] we proposed to more broadly analyze the key guiding principles for specific RNA-targeting. In this work, we report the discovery of distinct physicochemical, structural, and spatial properties of RNA-targeted bioactive ligands, which are expected to facilitate the rapid discovery of RNA-targeted chemical probes and subsequent evaluation of the therapeutic potential of non-ribosomal RNAs.…”

“…First, we gathered reports from reviews [10-11] and recent primary literature that described organic small molecule probes for non-ribosomal RNAs with evidence of both in vitro binding and target engagement in cell culture or animal models (SI-1). To focus on small organic molecules, peptides and oligonucleotides were omitted.…”

“…[12] Aminoglycosides were excluded due to known promiscuous RNA-binding behavior. [10c, 11b, 13] Molecules satisfying the selection criteria and highlighted in the conclusion of each report were included in the R NA - targeted BI oactive liga N d D atabase (R-BIND) (available as RBIND.xls). While compiling R-BIND, we identified two strategies utilized to target RNA in biological systems: monovalent small molecules (SM) and multivalent ligands (MV) (Figure 1).…”

Small Molecule-Based Pattern Recognition To Classify RNA Structure

“…26–29 In contrast to synthetic oligonucleotides, which are limited to targeting single-stranded sequences, small molecules offer the opportunity for three-dimensional structure-based targeting. 30–32 Many unanswered questions remain, however, regarding both the small molecule properties and the RNA structures that allow selective interactions, and insights into this relationship would facilitate both RNA-targeted drug discovery and the development of small molecule probes for RNA structure and function.…”