The Ribavirin Analog ICN 17261 Demonstrates Reduced Toxicity and Antiviral Effects with Retention of both Immunomodulatory Activity and Reduction of Hepatitis-Induced Serum Alanine Aminotransferase Levels

Abstract

The demonstrated utility of the nucleoside analog ribavirin in the treatment of certain viral diseases can be ascribed to its multiple distinct properties. These properties may vary in relative importance in differing viral disease conditions and include the direct inhibition of viral replication, the promotion of T-cell-mediated immune responses via an enhanced type 1 cytokine response, and a reduction of circulating alanine aminotransferase (ALT) levels associated with hepatic injury. Ribavirin also has certain known toxicities, including the induction of anemia upon chronic administration. To determine if all these properties are linked, we compared the D-nucleoside ribavirin to its L-enantiomer (ICN 17261) with regard to these properties. Strong similarities were seen for these two compounds with respect to induction of type 1 cytokine bias in vitro, enhancement of type 1 cytokine responses in vivo, and the reduction of serum ALT levels in a murine hepatitis model. In contrast, ICN 17261 had no in vitro antiviral activity against a panel of RNA and DNA viruses, while ribavirin exhibited its characteristic activity profile. Importantly, the preliminary in vivo toxicology profile of ICN 17261 is significantly more favorable than that of ribavirin. Administration of 180 mg of ICN 17261 per kg of body weight to rats by oral gavage for 4 weeks generated substantial serum levels of drug but no observable clinical pathology, whereas equivalent doses of ribavirin induced a significant anemia and leukopenia. Thus, structural modification of ribavirin can dissociate its immunomodulatory properties from its antiviral and toxicologic properties, resulting in a compound (ICN 17261) with interesting therapeutic potential.Ribavirin (1-␤-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a nucleoside analog that has demonstrated efficacy in treating viral disease as monotherapy (respiratory syncytial virus [RSV] [15]) and in combination with alpha interferon (IFN-␣) (hepatitis C virus [HCV] [27,36]). Ribavirin has multiple biologic properties that are favorable for treating viral diseases. It can directly inhibit the replication of many DNA and RNA viruses (38). More recently, studies have shown that it can also act as an immunomodulator and thus promote T-cell-mediated immunity against viral infection (18,25,30,39,40). The central focus of this effect of ribavirin is the augmentation of antiviral type 1 cytokine expression (interleukin-2 [IL-2], gamma interferon [IFN-␥], and tumor necrosis factor alpha [TNF-␣]) and concomitant suppression of type 2 cytokine levels by activated T cells in both human and murine systems. Finally, ribavirin, alone or in combination with IFN-␣, can lower serum alanine aminotransferase (ALT) levels during the course of treatment of HCV infection (11). Elevated serum ALT levels are a marker for liver damage and progressive hepatitis, and hence the ribavirin-mediated lowering of ALT levels is a distinct liver-specific effect of this nucleoside analog.The therapeutic use of ribavirin is restric...

Ribavirin-Resistant Mutants of Human Enterovirus 71 Express a High Replication Fidelity Phenotype during Growth in Cell Culture

“…Ribavirin has been shown to diminish viral protein translation and RNA replication via three activities: as a mutagen by incorporation into nascent viral RNA molecules (8)(9)(10)12), by the inhibition of IMP dehydrogenase (IMPDH), which results in a decrease in intracellular GTP levels (25)(26)(27), and by immunomodulatory effects, including a switch in the T-helper cell phenotype from type 2 to type 1 (28)(29)(30)(31)(32). It has been suggested that during virus replication in newly synthesized genomes, a decrease in cellular GTP levels may increase the frequency of ribavirin incorporation in newly synthesized genomes during virus replication through competitive inhibition (9, 10, 12, 13).…”

Mechanisms of Action of Ribavirin in Antiviral Therapies

“…A minimal direct antiviral activity of ribavirin against HCV and HBV in vitro (Clarysse et al, 1997;Tam et al, 2000) and minimal effect on HCV or HBV virus titres during ribavirin monotherapy (Reichard et al, 1993;Fried et al, 1994;Bodenheimer et al, 1997) suggests that ribavirin has other mechanisms of action. In contrast, the role of immunomodulation by ribavirin in chronic HCV infection may be significant.…”

“…Ribavirin may elicit indirect antiviral effects by (1) promoting T-cell mediated immunity against viral infection via the induction of antiviral type 1 cytokines such as IFN-γ, tumour necrosis factor-α (TNF-α) and interleukin-2 (IL-2), and the suppression of proviral type 2 cytokines such as IL-4 and IL-10 ( Tam et al, 1999aTam et al, ,b, 2000 or (2) by affecting the intracellular GTP concentration via inhibition of host inosine monophosphate dehydrogenase (IMPDH) (Streeter et al, 1973;Smith 1980), an effect which presumably inhibits viral RNA synthesis or DNA synthesis in proliferating lymphocytes (Peavy et al, 1980(Peavy et al, , 1981Marquardt et al, 1987). The immunodulatory effects of ribavirin on type 1 cytokines or IMPDH could have a beneficial impact on the immune responses against viral infection.…”

Treatment of recurrent hepatitis C

“…80 Unfortunately, in a recent Canadian randomized controlled multicenter study, high-dose intravenous HCIG, first administered in the anhepatic phase and continued for 48 weeks, had no effect on clinical or virological recurrence in 20 patients who underwent transplantation for HCV cirrhosis. 81 [82][83][84] Viramidine is a livertargeting ribavirin prodrug that is converted to active drug in the liver, thereby reducing RBC accumulation. Hopefully, one of these ribavirin analogues will improve the tolerability of combination therapy in liver transplant recipients.…”