Development of Systems for Delivery of Antiviral Drugs

摘要

Ribavirin, a broad-spectrum antiviral agent with potent activity in vitro against a number of important RNA viruses of military significance, is severely limited in its usefulness against virus-induced encephalitic diseases because it does not cross the blood-brain barrier well enough to achieve effective antiviral concentrations in the brain. Our efforts are directed toward the brain-specific delivery of ribavirin and other antiviral agents by means of a redox prodrug concept. The scope of the research program involves the synthesis of CNS-targeted prodrug esters of ribavirin and selenazole, pharmaco-kinetic, studies of drug distribution and sustained delivery of drug in the brain, and the evaluation of the therapeutic efficacy of these antiviral prodrugs compared with the parent drugs in the treatment of lethal Venezuelan equine encephalitis (VEE) virus and Japanese encephalitis (JE) virus infections in mice. We have synthesized the first of these prodrugs by a five-step route starting from ribavirin. In preliminary studies, this prodrug has protected mice from a lethal challenge of JE virus and was much superior in efficacy to the parent drug, which had no effect. Extraction and HPLC assay procedures necessary for the proposed pharmacokinetic studies with the ribavirin prodrug in mice have been developed.