Treating HCV with ribavirin analogues and ribavirin-like molecules.
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 dehydrogenase (IMPDH), which is the key step in de novo guanine synthesis, a requirement for viral replication. 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 require dose reduction, discontinuation or treatment with recombinant human erythropoietin. Dose reduction also appears to decrease sustained viral clearance rates. Newer IMPDH inhibitors are in various stages 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.
Gish
Robert G
RG
California Pacific Medical Center, Liver Transplant Program, Division of Hepatology and Complex GI, 2340 Clay Street, #223, San Francisco, CA 94612, USA. gishr@sutterhealth.org
D000998:Antiviral Agents / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D015394:Molecular Structure; D012254:Ribavirin / Q000009:adverse effects / Q000031:analogs & derivatives / Q000737:chemistry / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D012254:Ribavirin; D007168:IMP Dehydrogenase