title: Application of the phosphoramidate ProTide approach to the antiviral drug ribavirin.
abstract: Ribavirin is a nucleoside analogue with broad antiviral activity. Here we report the synthesis and biological evaluation of novel ribavirin ProTides designed to deliver the bioactive ribavirin monophosphate into cells. Some of the compounds display activity similar to the parent nucleoside against a range of viruses. Enzymatic, cell lysate and preliminary modeling studies have been performed to investigate the lack of enhancement of potency by the ProTides, and these indicate a failure at the final, amino acid cleavage step in the ProTide activation process, leading to inefficient release of the nucleoside monophosphate.
authors.affiliation: Welsh School of Pharmacy, Cardiff University, Cardiff CF10 3NB, UK.
authors.forename: Marco
authors.initials: M
authors.lastname: Derudas
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.forename: Lieve
authors.initials: L
authors.lastname: Naesens
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Christopher
authors.initials: C
authors.lastname: McGuigan
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D003588:Cytopathogenic Effect, Viral; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D010756:Phosphoric Acids / Q000138:chemical synthesis / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D012254:Ribavirin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D014780:Viruses / Q000187:drug effects
chemical_list: D000577:Amides; D000998:Antiviral Agents; C063306:HINT1 protein, human; D007202:Indicators and Reagents; D009419:Nerve Tissue Proteins; D010455:Peptides; D010756:Phosphoric Acids; D011355:Prodrugs; D012254:Ribavirin; C011067:phosphoramidic acid