Treating HCV with ribavirin analogues and ribavirin-like molecules

Abstract

Nucleos(t)ide analogues have proven useful in the treatment of viral infections. Ribavirin is a nucleoside, guanosine analogue, whose mechanisms of action include inhibition of inosine monophosphate dehy- drogenase(IMPDH), whichis thekey stepinde novoguaninesynthesis, arequirementforviralreplication. In combination with pegylated interferon alfa, ribavirin is the standard of care for the treatment of chronic hepatitis C today. However, the medication is associated with significant haemolytic anaemia, which may requiredosereduction,discontinuationortreatmentwithrecombinanthumanerythropoietin.Dosereduc- tionalsoappearstodecreasesustainedviralclearancerates.NewerIMPDHinhibitorsareinvariousstages of development. Viramidine, a liver-targeting prodrug of ribavirin, has demonstrated significant antiviral activity and erythrocyte-sparing properties. It is currently in Phase 3 trials. Clinical trials of merimepodib, another investigational IMPDH inhibitor, have completed enrolment for a Phase 2b study as a third medication for administration with pegylated interferon plus ribavirin. Although other IMDPH inhibitors also have antiviral activity, these medications appear best suited as immunosuppressive medications at this time.