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.