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.

Keywords: RNA therapeutics; antisense oligonucleotide; drug delivery; virus; virus-host interaction.

Figure 1

Molecular mechanisms of action of ASOs. ASOs can modulate the expression of target RNAs via two different mechanisms. Conventionally, ASOs cause RNase H-mediated cleavage of the target RNA. Additionally, 2′-O-modified ASOs and neutral DNA mimics (PMOs and PNAs) act as a steric-blocker to prevent the access of cellular factors to the target RNA. Adapted from [15], Springer Nature Limited, 2020.

Figure 2

Modifications, bioconjugations and delivery vehicles of ASOs. (A) Structures of backbone or sugar-modified ASOs as well as PNA and PMO oligomers. (B) Bioconjugates of ASOs include GalNac, Cholesterol, CpG DNA and CPP (R, arginine; X, 6-aminohexanoic acid). Vivo-PMO is an PMO covalently linked to an octa-guanidine dendrimer. (C) Representative delivery vehicles of ASOs include EPI-nanocarrier, liposome, LNP, and exosome. Adapted from [15], Spring Nature Limited, 2020; [20], MDPI, 2021.

Figure 3

ASOs targeting viruses. (A) Diagram shows viral life cycle from viral attachment and entry into host cells (1, 2), genome release from the capsid (3, 4), genome replication, transcription and protein expression (5, 6), and viral assembly and release (7, 8). (B) ASO-based antiviral strategies. Examples are given for four different types of viruses. Coronavirus (positive-strand RNA virus): ASOs target the transcription regulatory sequence (TRS) of the RNA genome (+RNA) to reduce viral subgenomic RNA production. Influenza (negative-strand RNA virus): ASOs target viral mRNAs to reduce the production of viral nucleoprotein and matrix protein. HBV (partially double-stranded DNA virus): ASOs target a conserved sequence of viral mRNAs to reduce the translation of viral proteins. HIV (retrovirus): ASOs bind to the viral genome to interfere with reverse transcription and hence reduce viral DNA production. Abbreviations: L, leader sequence; cRNA, complementary RNA; rcDNA, relaxed circular DNA; cccDNA, covalently closed circular DNA; pgRNA, pregenomic RNA.

Figure 4

ASOs targeting host factors. Viruses take advantage of host factors for their life cycle. (A) NPC1 participates in membrane fusion and RNP release of Ebola virus. (B) Raf-1 signaling promotes HCV replication and suppresses antiviral immunity. (C) MRJ-L is required for the production of subgenomic RNA and mRNAs of RSV and facilitates the nuclear entry of the HIV preintegration complex. (D) miR-122 stabilizes the genome of HCV and promotes viral replication. Therefore, ASOs that suppress the expression of these host factors or block miRNAs can inhibit viral entry or viral genome amplification or protein production. Meanwhile, ASOs may restore antiviral activity of infected cells by suppressing the expression of certain viral or host factors. Abbreviations: ISRE, interferon-stimulated response element; ISG, interferon-stimulated gene; PIC, preintegration complex; IRES, internal ribosome entry site.