Ribavirin for the treatment of chronic hepatitis C virus infection: a review of the proposed mechanisms of action
Highlights
► Ribavirin is a triazole nucleoside that is used in combination with pegylated interferon-α for the treatment of HCV infections. ► Ribavirin is extensively being used to treat HCV-infected patients. ► The mechanism by which the molecule contributes to an antiviral response in these patients remains elusive. ► Ribavirin may exert its antiviral activity via a number of distinct mechanisms.
Introduction
Four decades after its discovery [1], the triazole nucleoside ribavirin (Virazole™, Virazid™, Figure 1a) still proves useful for the treatment of a number of viral infections [2] and may also be promising as an anticancer drug [3]. However, the therapeutic efficacy of ribavirin is overshadowed by a dose-dependent reversible anaemia [4, 5] (see Box 2). Ribavirin has been approved for the treatment of infections with the respiratory syncytial virus [3], the Lassa fever virus [6] and, in combination with (pegylated) interferon, for the treatment of chronic infections with the hepatitis C virus (HCV) [7, 8, 9, 10, 11]. HCV is a positive-stranded RNA virus that belongs to the family of the Flaviviridae. Worldwide, HCV causes chronic liver infections in an estimated 170 million people, who are all at high risk of developing fatal liver disease. The effect of ribavirin monotherapy on chronic HCV infection was reported for the first time in 1991 [12, 13]. Ribavirin was shown to cause only a transient antiviral effect during treatment and no significant effect on liver-related morbidity or mortality [13]. However, parallel trials using ribavirin (1000 or 1200 mg/day) in combination with interferon-alfa (3 million international units three time/week) resulted in an improved treatment outcome [7, 8, 9, 10, 11]. This therapy was further optimised by the introduction of pegylated interferon-alfa, which has a longer half-life allowing once weekly dosing [14, 15]. The current standard of care (SOC) for the treatment of chronic HCV consists of once-weekly subcutaneous peginterferon-alfa and twice-daily oral ribavirin. On average, the success rate of SOC is 50% for patients infected with HCV genotype 1 [16]. By implementing a pharmacogenomic approach, the therapy can be tailored to a particular patient, thereby ensuring a maximal clinical benefit and minimal side-effects (see Box 1). In May of 2011, the first direct acting anti-HCV agents (i.e. the NS3 protease inhibitors Boceprevir [17, 18, 19, 20] and Telaprevir [21, 22]) became availablefor the treatment of chronic HCV infections, in combination with the current SOC [23]. Direct acting anti-HCV agents [16] are specifically optimised to inhibit the function of viral proteins either directly (e.g. Tegobuvir [24] as polymerase inhibitor), or indirectly by preventing interactions with essential host cell co-factors (i.e. Debio-025 [25, 26, 27, 28]). In the future, interferon sparing regimens will probably consist of combinations of three or four direct acting anti-HCV agents and will almost certainly replace the current SOC. However, the PROVE trials [21] show that ribavirin may for some time remain an essential component of at least some combinations to prevent viral relapse. Ribavirin is likely to outlast interferon for the treatment of HCV.
Section snippets
Potential mechanism(s) of action of ribavirin against HCV
Although ribavirin is extensively used to treat patients with HCV-infection, the mechanism by which the molecule contributes to an antiviral response in these patients remains largely elusive. The antiviral activity of ribavirin is ascribed to a combination of different mechanism(s) (see Figure 1): (i) immunomodulation, (ii) modulation of the interferon-stimulated gene (ISG) expression, (iii) inhibition of inosine 5’-monophosphate dehydrogenase (IMPDH) by ribavirin 5’-monophosphate (RMP), (iv)
Inosine 5′-monophosphate dehydrogenase inhibition
One of the earliest reported mechanisms of action of ribavirin is the inhibition of cellular inosine 5′-monophosphate dehydrogenase. IMPDH has a key role in guanine nucleotide biosynthesis, namely the conversion of inosine 5′-monophosphate to xanthine 5′-monophosphate, an intermediate in the de novo synthesis of guanosine [29] (see Box 2). Hence, this enzyme modulates intracellular guanine (deoxy)nucleotide pools and thus has an important impact on plenty of cellular processes, including the
Inhibition of RNA-dependent RNA polymerase and viral mutagen
RNA-dependent RNA polymerase (RdRp) or the NS5B protein of HCV is responsible for the replication of the viral genome. RdRp can be inhibited directly by ribavirin 5′-triphosphate (RTP) or can be incorporated (as RMP) in the viral genome leading to viral mutagenesis [37••]. A more detailed explanation of both mechanisms is presented in Box 3. A number of studies lent support to the hypothesis that ribavirin acts as a mutagen for HCV during SOC; whereas other studies argue against such a
Modulation of the immune system by ribavirin
Chronic hepatitis C is believed to be mainly the result of failure of the immune system to mount a vigorous cellular response needed to clear the virus from the liver [40]. Ribavirin might aid in preserving or increasing the vigorous T helper 1 (Th1CD4(+)) responses needed to clear HCV infection [the Th2CD4(+) response is associated with tolerance and chronic infection] [41•]. However, it remains a matter of debate whether the clinically beneficial effect of ribavirin in HCV-infected patients
Induction of interferon-stimulated gene expression by ribavirin
Upon infection, cells mount an innate immune response to protect them from the virus and to ‘warn’ neighbouring cells by means of interferon. Once interferon binds to its receptor, a signal cascade is triggered that results in the expression of interferon-stimulated genes (ISGs), leading to the ‘antiviral state’ [44]. Apart from some well-studied examples (i.e. the protein kinase R; 2′5′-oligoadenylate synthetase and mx GTPases) the function of most ISGs has largely remained unexplored [44].
Ribavirin as an inhibitor of eIF4E
A sixth possible anti-HCV mechanism of ribavirin, which has not been formally proposed before, may be based on its anti-tumoral activity. Ribavirin is believed to inhibit eIF4E, the rate-limiting component of the translation initiation complex, by functioning as an analogue of the 7-methyl-guanosine mRNA cap [54••]. The HCV genome is not capped and consequentially does not require eIF4E for translation of the viral genome [55]. However, ribavirin may interfere with HCV replication by modifying
Conclusion
Although inhibition of IMPDH activity is not likely to be the mechanism by which ribavirin inhibits HCV replication in the infected patient, it seems, in one way or another, linked with most of the other proposed mechanism of actions. Different intracellular GTP concentrations have an impact on differentiation and apoptosis by triggering a myriad of signal pathways [61•]. Hence, IMPDH inhibition by ribavirin can hardly be unlinked from most of the other proposed mechanism of actions. In fact,
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported by a postdoctoral fellowship from the Research Foundation Flanders-FWO to Jan Paeshuyse, the IWT-SBO project #100042 and by grant G.0728.09N of the Research Foundation Flanders-FWO.
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2020, Drug Discovery TodayCitation Excerpt :Given that ribavirin mimics inosine, it binds to the active site of IMPDH, thus reducing the production of GMP, which is essential for RNA replication [85]. This significant reduction in GTP concentration (by 90%) might improve the incorporation of ribavirin triphosphate by RdRp, which might either cause an increase in random mutations in the RNA strand or result in RNA chain termination and blocking of viral RNA synthesis [86]. Moreover, given that ribavirin is a guanosine analog, it might also interact with enzymes implicated in the synthesis of the 7-methylguanosine RNA cap structure that prevents RNA degradation and is essential for RNA translation [87].
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