Antisense Oligonucleotide-Based Therapy of Viral Infections

Abstract

Nucleic acid-based therapeutics have demonstrated their efficacy in the treatment of various diseases and vaccine development. Antisense oligonucleotide (ASO) technology exploits a single-strand short oligonucleotide to either cause target RNA degradation or sterically block the binding of cellular factors or machineries to the target RNA. Chemical modification or bioconjugation of ASOs can enhance both its pharmacokinetic and pharmacodynamic performance, and it enables customization for a specific clinical purpose. ASO-based therapies have been used for treatment of genetic disorders, cancer and viral infections. In particular, ASOs can be rapidly developed for newly emerging virus and their reemerging variants. This review discusses ASO modifications and delivery options as well as the design of antiviral ASOs. A better understanding of the viral life cycle and virus-host interactions as well as advances in oligonucleotide technology will benefit the development of ASO-based antiviral therapies.

Secondary Structure of Influenza A Virus Genomic Segment 8 RNA Folded in a Cellular Environment

“…The development of such technology is especially important, as more and more drug-resistant influenza strains evolved with time [ 58 ]. Different RNA-based nucleic acid therapies have been proposed in the case of RNA viruses [ 59 ]. Depending on the mechanism of the inhibition, these can block the replication processes of the virus by creating steric blockades or lead to RNase H cleavage of targeted RNA [ 57 ].…”

Translational Control of COVID-19 and Its Therapeutic Implication

“…Targeting conserved RNA structures and sequences of SARS-CoV-2 is an alternative approach to inhibiting viral infection and progression ( 209 , 210 ). The most well-known examples are antisense oligonucleotides (ASOs), which contain modifications at their positions, such as 2-O-methyl (2-OME), 2-O-methoxy (2-MOE), locked nucleic acid (LNA), morpholino, or other nucleotide modifications, which may increase RNA base pairing, metabolic stability, and/or delivery ( 209 , 211 , 212 ). Circular RNAs (circRNAs) can also be engineered as antisense RNAs to disrupt SARS-CoV-2 genome expression and viral proliferation ( 213 ).…”

“…These antisense-RNAs form stable hybrids with their target RNAs, which cause target RNAs cleavage/degradation or block mRNA processing or translation ( 213 – 215 ). Antisense DNA oligonucleotide forms a hybrid with the target RNA and induces cleavage of RNA by RNase H, an endonuclease that cleaves the RNA-DNA strands, limiting the synthesis of the encoded protein ( 212 ). Another study showed that in a pseudovirus infection model, 2’-OME/SP-ASO conjugated with four 2’-5’-oligonucleotides that can induce RNase L-mediated cleavage and degradation of SARS-CoV-2 envelope and spike, thereby effectively inhibiting the spread of the virus ( 216 ).…”

Internal Ribosome Entry Site (IRES)-Mediated Translation and Its Potential for Novel mRNA-Based Therapy Development

“…It is also possible to target ITAFs with specific ASOs that inhibit ITAF expression and, hence, modulate IRES activity depending on the effect of the ITAF on the regulated IRES—activator ITAF ( Figure 2 B) or inhibitory ITAF ( Figure 2 C). Several ASOs have already been designed to target cellular host factors needed to regulate IRES-mediated translation upon viral infection (reviewed in [ 125 ]). However, this approach could be more complex and less accurate since each ITAF can regulate more than one IRES simultaneously, creating a general effect on several pathways, instead of mediating a specific and desired interaction and/or IRES [ 114 ].…”