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Ribavirin is a guanosine analogue that produces broad-spectrum activity against different RNA and DNA viruses. Four decades after its discovery this drug still proves useful for the treatment of a number of viral infections and may also be promising as an anticancer drug. Nevertheless, the uncertain nature of ribavirin’s antiviral mechanism of action has been a stumbling block to developing more efficacious derivatives for clinical usage.
Ribavirin was first discovered and developed in 1970 by researchers from the International Chemical & Nuclear Corporation (ICN), today known as Valeant Pharmaceuticals. Chemists Joseph T. Witkovski and Ronald K. Robins had a main role in synthesizing this compound.
Ribavirin was initially approved for use in humans to treat pediatric respiratory syncytial virus infections. Through the years its efficacy for this indication has proved to be controversial, as shown in a number of studies with conflicting results.
In 1972 it was reported that ribavirin was active against different DNA and RNA viruses in culture systems and animals. Some examples were herpes simplex, vaccinia virus, measles, influenza A and B, parainfluenza, rhabdoviruses, arenaviruses, bunyaviruses and possibly retroviruses.
Research towards understanding the exact antiviral mechanism of ribavirin has a complex and contentious history, with a myriad of distinct mechanisms being proposed. In 2001 the mechanism was demonstrated by Craig E. Cameron, Shane Crotty and Raul Andino; their poliovirus experiments hinted that ribavirin's antiviral activity is exerted via lethal mutagenesis.
Severson and colleagues investigated the effect of ribavirin treatment on Hantaan virus. An observed decrease in viral mRNA and protein production was attributed to mutagenesis during transcription, leading to unstable or nonfunctional mRNAs. Moreover, a high number of insertions were found.
First attempts to use ribavirin as monotherapy to treat hepatitis C was recorded in the early 1990s. Pilot studies were undertaken due to the fact that ribavirin previously demonstrated its broad-spectrum antiviral activity against RNA viruses, and that HCV is related to flavivirus with a positive sense RNA genome.
Patients treated with ribavirin monotherapy demonstrated improvements in serum alanine aminotransferase levels with certain indications that patients infected with HCV genotype 2/3 may be more responsive. On the other hand, little effect has been shown on HCV RNA levels, with no patients achieving viral clearance.
There were no other significant advancements in the treatment of hepatitis C until 1998, when the combination of ribavirin and interferon-alpha gained approval. Clinically, ribavirin showed a small, additive antiviral effect in combination with interferon, but its main effect was dose-dependent prevention of virological relapse.
Triple therapy regimens (i.e. the use of ribavirin with telaprevir and boceprevir) gained approval in May 2011. The role of ribavirin in success of this approach appeared to be on the prevention of relapse and the emergence of both low-level and high-level protease inhibitor resistance.