Celgosivir, an alpha-glucosidase I inhibitor for the potential treatment of HCV infection.
Celgosivir, in development by MIGENIX Inc for the treatment of HCV infection, is an oral prodrug of the natural product castanospermine that inhibits alpha-glucosidase I, an enzyme that plays a critical role in viral maturation by initiating the processing of the N-linked oligosaccharides of viral envelope glycoproteins. Celgosivir is well absorbed in vitro and in vivo, and is rapidly converted to castanospermine. Celgosivir has a novel mechanism of action (ie, host-directed glycosylation), and demonstrates broad antiviral activity in vitro. The agent is not efficient as a monotherapy for the treatment of HCV, but has demonstrated a synergistic effect in combination with the current standard of care, PEGylated IFNalpha2b plus ribavirin, both in vitro and in phase II clinical trials. At the time of publication, a phase II trial was underway to investigate the safety, tolerability and antiviral effect of celgosivir in combination with PEGylated IFNalpha2b plus ribavirin for up to 1 year in patients with chronic HCV infection. Celgosivir may prove to be a valuable component for combination therapy and may help to prevent the apparition of drug resistance. Long-term toxicity studies are necessary to confirm the safety of this novel drug in humans.
Durantel
David
D
INSERM U871, Molecular Physiopathology and New Treatment of Viral Hepatitis, 151 cours Albert Thomas, Cedex 03 Lyon, France. david.durantel@inserm.fr
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D065089:Glycoside Hydrolase Inhibitors; D016174:Hepacivirus / Q000187:drug effects; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D007212:Indolizines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000627:therapeutic use; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011994:Recombinant Proteins; D012254:Ribavirin / Q000627:therapeutic use; D000520:alpha-Glucosidases; D054836:Indolizidines
D000998:Antiviral Agents; D065089:Glycoside Hydrolase Inhibitors; D007212:Indolizines; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D011355:Prodrugs; D011994:Recombinant Proteins; D012254:Ribavirin; D000520:alpha-Glucosidases; C070715:celgosivir; D054836:Indolizidines; C042059:glucosidase I; C417083:peginterferon alfa-2b