What future for ribavirin?

Shiffman, Mitchell L.

doi:10.1111/j.1478-3231.2008.01936.x

Cited by 26 publications

(20 citation statements)

References 36 publications

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“…6 Thus, RBC samples were treated with phosphatase, which converted phosphorylated ribavirin to ribavirin; total ribavirin concentration measurement reflects the sum of ribavirin and phosphorylated ribavirin. Meanwhile, pilot studies here indicated that non-phosphorylated ribavirin was the predominant form in the liver sample (Figure S1).…”

Section: Resultsmentioning

confidence: 99%

“…4, 5 However, its usefulness is limited by the dose dependent hemolytic anemia, which results in dose reduction or treatment termination in approximate 20% and 5% treated patients, respectively. 6 This serious side effect is caused by ribavirin accumulation in the anucleate red blood cells (RBC), where ribavirin undergoes irreversible phosphorylation. Ribavirin phosphorylation in RBCs causes depletion of ATP in a competitive manner and exerts oxidative damage on the cell membrane.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Evaluation of Bile Acid–Ribavirin Conjugates as Prodrugs to Target the Liver

Dong

Guo

et al. 2015

Journal of Pharmaceutical Sciences

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Ribavirin is used to treat hepatitis C but causes serious hemolytic anemia. The objective of the study was to develop a ribavirin prodrug to achieve liver specific drug delivery and to reduce its off-target effect in red blood cells (RBC). The approach aimed to target the human sodium taurocholate cotransporting polypeptide (NTCP), which is a bile acid transporter predominately expressed in the liver. Six prodrugs with ribavirin conjugation at C-3 or C-24 of the bile acids were synthesized. In vitro uptake studies indicated that all six prodrugs were NTCP substrates. Metabolic studies in vitro indicated that ribavirin-L-Val-GCDCA was able to release ribavirin in the mouse liver S9 fraction. Additionally, in vitro studies showed that ribavirin in RBC was reduced by 16.7 fold from prodrug compared to parent drug incubation. Moreover, almost no prodrug was present in RBC. In vivo study in mice also showed that ribavirin-L-Val-GCDCA could provide almost the same ribavirin exposure in the liver as ribavirin administration, but with about 1.8-fold less exposure of ribavirin in RBC, plasma, and kidney. Overall, the study suggested that ribavirin-L-Val-GCDCA has the potential to achieve ribavirin specific liver delivery.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of Bile Acid–Ribavirin Conjugates as Prodrugs to Target the Liver

Dong

Guo

et al. 2015

Journal of Pharmaceutical Sciences

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“…Besides the very high costs associated with these treatments, other issues include variability in activity across different genotypes, such as genotype 3 that can result in failure to achieve SVR [3]. If RBV is required, significant side effects can occur, such as haemolytic anaemia [4]. Treatment with DAAs can also result in resistant viruses as targeting viral proteins puts direct selective pressure for resistant mutants.…”

Section: Introductionmentioning

confidence: 99%

Allosteric heat shock protein 70 inhibitors block hepatitis C virus assembly

Khachatoorian

Riahi

Ganapathy

et al. 2016

International Journal of Antimicrobial Agents

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The human molecular chaperones heat shock protein 70 (Hsp70) and heat shock cognate protein 70 (Hsc70) bind to the hepatitis C viral nonstructural protein 5A (NS5A) and regulate its activity. Specifically, Hsp70 is involved in NS5A-augmented internal ribosomal entry site (IRES)-mediated translation of the viral genome, whilst Hsc70 appears to be primarily important for intracellular infectious virion assembly. To better understand the importance of these two chaperones in the viral life cycle, infected human cells were treated with allosteric Hsp70/Hsc70 inhibitors (AHIs). Treatment with AHIs significantly reduced the production of intracellular virus at concentrations that were non-toxic to human hepatoma Huh7.5 cells. The supernatant of treated cultures was then used to infect naïve cells, revealing that AHIs also lowered levels of secreted virus. In contrast to their effects on virion assembly, AHIs did not impact the stability of NS5A or viral protein translation in IRES assays. These results suggest that Hsc70 plays a particularly important and sensitive role in virion assembly. Indeed, it was found that combination of AHIs with a peptide-based viral translation inhibitor exhibited additive antiviral activity. Together these results suggest that the host Hsc70 is a new antiviral target and that its inhibitors utilise a new mechanism of action.

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“…Efforts to replace RBV with taribavirin, a RBV prodrug formerly known as viramidine, have been unsuccessful (1). Although HCV protease and polymerase inhibitors are promising new antivirals, RBV will continue to be a critical part of combination therapy because eliminating RBV from telaprevir-IFN therapy significantly reduced response rates (26,43).…”

mentioning

confidence: 99%

Host-Based Ribavirin Resistance Influences Hepatitis C Virus Replication and Treatment Response

Ibarra

Jain

Pfeiffer

2011

J Virol

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Many individuals infected with hepatitis C virus (HCV) develop a chronic infection, and of those who are treated with pegylated interferon and ribavirin (RBV), many do not respond. While the nucleoside analog RBV improves treatment outcome, and will likely be an important component of therapy with next-generation viral inhibitors, RBV's mechanism is controversial. Most of RBV's proposed mechanisms require RBV import into cells. Therefore, we explored whether host-based RBV resistance develops through reduced cellular uptake, akin to chemotherapy resistance in some cancers. We examined the effect of host-based RBV resistance on HCV replication in cultured hepatoma Huh7.5 liver cells and whether RBV resistance develops in HCV patients. When Huh7.5 cells were exposed to RBV, resistance developed through reduced RBV uptake via the ENT1 nucleoside transporter and antiviral efficacy was reduced. The uptake defect in RBV-resistant cells was specific to RBV, since transport of another ENT1 substrate, cytidine, was unaffected. Importantly, RBV uptake significantly declined in HCV patient peripheral blood mononuclear cells (PBMCs) following 4 weeks of therapy. Furthermore, maintenance of RBV uptake correlated with rapid treatment response. Our results uncovered a novel form of antiviral drug resistance and suggest that host-based RBV resistance develops in HCV patients undergoing therapy and that maintenance of RBV uptake may contribute to rapid viral clearance.

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What future for ribavirin?

Cited by 26 publications

References 36 publications

Synthesis and Evaluation of Bile Acid–Ribavirin Conjugates as Prodrugs to Target the Liver

Synthesis and Evaluation of Bile Acid–Ribavirin Conjugates as Prodrugs to Target the Liver

Allosteric heat shock protein 70 inhibitors block hepatitis C virus assembly

Host-Based Ribavirin Resistance Influences Hepatitis C Virus Replication and Treatment Response

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