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.

Figure 1

Aminoglycosides such as neomycin and kanamycin, and planar intercalators including derivatives of acridine, phenazine, and phenothiazine are promiscuous binders of multiple RNA targets.

Figure 2

Linezolid is an oxazolidinone antibiotic (Zyvox^®) that binds at the peptidyl transferase center in the 23S rRNA of the bacterial 50S ribosomal subunit and inhibits translation initiation.23 See the Box 1 for an explanation of molecular properties shown here for linezolid.

Figure 3

Secondary structure of the HIV‐1 TAR (a) and RRE stem‐loop IIB (b) RNA targets.

Figure 4

The HCV IRES subdomain IIa RNA target. (a) Secondary structure of the subdomain IIa internal loop. Residue numbering corresponds to the HCV genome sequence. (b) Crystal structure of the subdomain IIa RNA in complex with the benzimidazole IRES inhibitor 6 (Table 3).42 The ligand is shown in yellow stick representation. Positions of two magnesium ions are indicated by green spheres. (c) Target recognition by hydrogen bonding and partial intercalation of benzimidazole 6 in the subdomain IIa RNA complex crystal structure. Structure image was prepared from PDB coordinate file 3TZR.42

Figure 5

Secondary structure of the SARS CoV frameshifting pseudoknot RNA.

Figure 6

The Influenza A RNA promoter target. (a) Secondary structure of the RNA promoter. A construct used for ligand binding screening by NMR was derived by adding a stable tetraloop. Residue numbering refers to the NMR construct. (b) Model of a ligand‐target complex derived by NMR spectroscopy of RNA promoter bound to compound 11 (Table 5).48 The ligand is shown in yellow stick representation. The added tetraloop is indicated in gray. (c) Detail view of the ligand binding site in the NMR model, showing hydrogen atoms of the ligand 11. Structure images were prepared from PDB coordinate file 2LWK.48