Table 1.
Compounds and approaches used to target IRESs.
| Compound | Mechanism of action | Advantages | Disadvantages | Reference |
|---|---|---|---|---|
 |
Guide destruction of IRESs/RNAs via an RNAse H-dependent degradation mechanism, or prevent IRESs interaction with the components of the translation machinery (40S ribosomal subunits, ITAFs, etc.) | Easy to design, prepare/obtain | Reduced efficiency of delivery, low intracellular stability, may cause proinflammatory responses | (31, 32, 35, 36, 41, 66) |
 |
Prevent IRESs interaction with the components of the translation machinery (40S ribosomal subunits, ITAFs, etc.) | Enhanced stability (these compounds are not substrates of RNAse H) | Reduced efficiency of delivery may cause proinflammatory responses | (31, 32, 35, 36, 41, 66) |
 |
Prevent IRESs interaction with the components of the translation machinery (40S ribosomal subunits, ITAFs, etc.) | Enhanced stability, enhanced affinity toward target RNA sequences | Reduced efficiency of delivery, intracellular trafficking. May be toxic | (36, 37, 67–71) |
 |
Prevent IRESs interaction with the components of the translation machinery (40S ribosomal subunits, ITAFs, etc.) | Enhanced stability, enhanced affinity toward target RNA sequences | Reduced efficiency of delivery, intracellular trafficking. May be toxic | (36, 37, 67–71) |
 |
Sterically block target RNAs. Prevent IRESs interaction with the components of the translation machinery (40S ribosomal subunits, ITAFs, etc.) | Enhanced stability, reduced toxicity | Reduced efficiency of delivery, intracellular trafficking. Specificity may be an issue | (42, 43) |
| Antisense: siRNA, shRNA (RNAi) | Guide destruction of target IRESs/RNAs or mRNAs coding for ITAFs via RISC-dependent mechanism | Easy to design, prepare/obtain | Reduced stability and efficiency of delivery. Specificity may be an issue. May activate PKR | (41, 44–47, 72–75) |
| RNA aptamers, ribozymes (Rz), DNAzymes (Dz) | Cleave target IRESs/RNAs. | High selectivity | Design process may be complicated | (48–53) |
| Short peptides, small molecules | Prevent IRESs interaction with the components of the translation machinery (40S ribosomal subunits, ITAFs, etc.) | Considered as the preferred form of drug therapies. Allow lead optimization | Sometimes mechanism of action is difficult to establish and characterize, e.g., when small molecules have been selected during high-throughput screening | (54–62, 76–78) |