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Review
. 2013 Dec 21;19(47):8949-62.
doi: 10.3748/wjg.v19.i47.8949.

Prospects for nucleic acid-based therapeutics against hepatitis C virus

Chang Ho Lee  1 , Ji Hyun Kim  1 , Seong-Wook Lee  1
Affiliations
Review

Prospects for nucleic acid-based therapeutics against hepatitis C virus

Chang Ho Lee et al. World J Gastroenterol. .

Abstract

In this review, we discuss recent advances in nucleic acid-based therapeutic technologies that _target hepatitis C virus (HCV) infection. Because the HCV genome is present exclusively in RNA form during replication, various nucleic acid-based therapeutic approaches _targeting the HCV genome, such as ribozymes, aptamers, siRNAs, and antisense oligonucleotides, have been suggested as potential tools against HCV. Nucleic acids are potentially immunogenic and typically require a delivery tool to be utilized as therapeutics. These limitations have hampered the clinical development of nucleic acid-based therapeutics. However, despite these limitations, nucleic acid-based therapeutics has clinical value due to their great specificity, easy and large-scale synthesis with chemical methods, and pharmaceutical flexibility. Moreover, nucleic acid therapeutics are expected to broaden the range of _targetable molecules essential for the HCV replication cycle, and therefore they may prove to be more effective than existing therapeutics, such as interferon-α and ribavirin combination therapy. This review focuses on the current status and future prospects of ribozymes, aptamers, siRNAs, and antisense oligonucleotides as therapeutic reagents against HCV.

Keywords: Antisense oligonucleotide; Aptamer; Hepatitis C virus; Nucleic acid-based therapeutics; Ribozyme; siRNA.

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Figures

Figure 1
Figure 1
Overview of hepatitis C virus life cycle and antiviral _target. The hepatitis C virus (HCV) life cycle includes entry, un-coating, replication, translation, processing of poly-proteins, assembly, and release. HCV has an RNA genome which replicates and is translated in the cytoplasm. Various nucleic acid-based therapeutics _target viral or host factors during the HCV infection as follows: (1) Ribozymes cleave or reprogram HCV RNA, sequence-specifically, thus inhibiting HCV RNA expression or inducing new therapeutic gene expression; (2) Aptamers can _target to receptors (CD81, CLDN1, OCNL, SR-B1), which are needed for HCV entry, or to HCV regulatory proteins. Therefore, aptamers function as decoys during HCV entry or during replication to inhibit the viral life cycle; (3) siRNAs _target the HCV genome as well as host factors, and can cleave and/or suppress translation of _target RNA, sequence-specifically, through the RNAi induced silencing complex (RISC); (4) Antisense oligonucleotides induce inhibition of HCV gene expression through RNase H-dependent degradation of hybridized HCV RNA or by blocking access to cellular machinery necessary for the HCV translation; (5) MiR-122 is a host factor which regulates HCV replication. MiR-122 is incorporated into microRNA associated stabilizing complex (MASC) and increases HCV replication through binding to the HCV 5’ IRES; and (6) Anti-miR-122 down-regulates miR-122, inhibiting HCV replication. Lines represent the following: inhibition of replication (solid line), translation (short dashed line) and entry (long dashed line). An arrow indicates augmentation (black arrow) or the direction (gray arrow) of replication. Nucleic acid-based therapeutic molecules are shown as follows: ribozyme (pink), aptamer (blue), siRNA (sky blue), anti-sense (red) and anti-miR-122 (orange). CD81: Cluster of differentiation 81; CLDN1: Claudin-1; OCLN: Occludin; SR-BI: Scavenger receptor BI; ER: Endoplasmic reticulum.
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